Next Article in Journal
Estrogen Signals through ERβ in Breast Cancer; What We Have Learned since the Discovery of the Receptor
Previous Article in Journal
Exploring Emerging Therapeutic Targets and Opportunities in Neuroendocrine Tumors: Updates on Receptor Tyrosine Kinases
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Receptors
Volume 3
Issue 2
10.3390/receptors3020009
receptors-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease

by
Ichiro Kawahata
1,*,
David I. Finkelstein
2 and
Kohji Fukunaga
1
1
Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan
2
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia
*
Author to whom correspondence should be addressed.
Receptors 2024, 3(2), 155-181; https://doi.org/10.3390/receptors3020009
Submission received: 31 December 2023 / Revised: 5 February 2024 / Accepted: 9 April 2024 / Published: 12 April 2024
Versions Notes

Abstract

:
Understanding the intricate role of dopamine D1–D5 receptors is pivotal in addressing the challenges posed by the aging global population, as well as by social stress and advancing therapeutic interventions. Central to diverse brain functions such as movement, cognition, motivation, and reward, dopamine receptors are ubiquitously distributed across various brain nuclei. This comprehensive review explores the nuanced functions of each dopamine receptor, D1, D2, D3, D4, and D5, in distinct brain regions, elucidating the alterations witnessed in several neurological and psychiatric disorders. From the substantia nigra and ventral tegmental area, crucial for motor control and reward processing, to the limbic system influencing emotional responses, motivation, and cognitive functions, each brain nucleus reveals a specific involvement of dopamine receptors. In addition, genetic variations in dopamine receptors affect the risk of developing schizophrenia and parkinsonism. The review further investigates the physiological significance and pathogenic impacts of dopamine receptors in critical areas like the prefrontal cortex, hypothalamus, and striatum. By unraveling the complexities of dopamine receptor biology, especially those focused on different brain nuclei, this review provides a foundation for understanding their varied roles in health and disease, which is essential for the development of targeted therapeutic strategies aimed at mitigating the impact of aging and mental health on neurological well-being.

1. Introduction

The aging global population presents a profound challenge to healthcare systems worldwide, necessitating a deeper understanding of the molecular intricacies governing neurodegenerative processes. Among the key players in the intricate network of neuronal signaling are dopamine receptors, integral components orchestrating a symphony of physiological responses. Dopamine, a neurotransmitter renowned for its central role in motor control, reward mechanisms, and cognitive functions, engages a diverse family of receptors, each with distinctive functions and implications for human health. Dysregulation and genetic variations in dopamine receptors affect the risk of dopaminergic pathogenesis, including mental and movement disorders.
Since there have been few reviews that have presented the function of dopamine receptors based on different brain nuclei, this review focuses on the distribution of dopamine D1–D5 receptors, based on each brain nucleus, their physiological significance, and their relevance to disease. Therefore, this review aims to comprehensively explore the multifaceted roles of dopamine D1, D2, D3, D4, and D5 receptors, delving into their intricate functions within the central nervous system, particularly in the different nuclei of the brain, and the implications in disease. Beyond their well-established contributions to motor coordination, emerging evidence implicates these receptors in a spectrum of neurodegenerative diseases, including motor and cognitive dysfunctions, as well as psychiatric disorders, including Parkinson’s disease, dystonia, schizophrenia, and attention-deficit/hyperactivity disorder (ADHD).
As we stand at the intersection of an aging population and unprecedented strides in therapeutic development, elucidating the nuanced involvement of dopamine receptors in health and disease becomes paramount. Thus, through an in-depth examination of the current literature, we seek to provide a comprehensive overview of the physiological impacts of nuclei-dependent dopamine D1–D5 receptors, shedding light on their potential as therapeutic targets, and unraveling the complexities that underscore their pivotal role in neurological well-being.

2. Types, Characteristics, and Regulation of Dopamine Receptors

Dopamine receptors, integral components of the central nervous system, form a diverse class of G protein-coupled receptors that mediate the actions of dopamine. Categorized into D1-like (including D1 and D5) [1,2,3,4,5] and D2-like (encompassing D2, D3, and D4) receptor families [6,7,8,9,10], these receptors exhibit distinct structural and functional characteristics. D1-like receptors, such as D1 and D5, predominantly elicit excitatory effects by activating adenylate cyclase and increasing intracellular cyclic AMP (cAMP) levels [11]. Conversely, D2-like receptors, including D2, D3, and D4, typically exert inhibitory effects by inhibiting adenylate cyclase and decreasing cAMP levels [12]. The distribution of these receptors is heterogeneous throughout the brain, with specific subtypes being concentrated in different regions, thus contributing to their diverse functional roles (Table 1).
D1 receptors are predominantly abundant in the striatum, nucleus accumbens, the substantia nigra pars reticulata, the olfactory bulb, and cortex [1,2,3,5,6,13,14]. In contrast, D2 receptors, with the variants D2 short type (D2S) and D2 long type (D2L), are distributed in various brain regions [6,7,8,9,10,59,60], including the striatum, nucleus accumbens, and olfactory tubercle at a high density, and in the hippocampus, amygdala, hypothalamus, and cortical regions to a lower extent [31,32,33,34]. Dopamine D2L receptors are primarily found postsynaptically, but are also localized in the presynaptic terminal [33], which are abundantly expressed in areas of the brain associated with motor control, such as the striatum and substantia nigra [8,61,62]. Postsynaptic D2L receptors play a key role in inhibiting cAMP production when dopamine binds. This inhibition is associated with a reduction in neuronal excitability. In contrast, D2S receptors are found both presynaptically on the neuron releasing dopamine, and postsynaptically. The presynaptic D2S receptor acts as an autoreceptor [33,63,64,65]. When dopamine binds to D2S receptors on presynaptic neurons, it inhibits further dopamine release, acting as a feedback mechanism [33,63,65]. These autoreceptors are found on the soma and dendrites of mesencephalic dopaminergic neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), as well as on their axon terminals in projection areas, including striatum and nucleus accumbens [31,34]. Interestingly, D2S receptors are predominantly localized at the plasma membrane, whereas D2L receptors are also observed in the perinuclear region around the Golgi apparatus, and only D2L receptors have the ability to bind type 3 fatty acid-binding proteins (FABP3) [66]. Dopamine D3 receptors are prominent in the nucleus accumbens, insular cortex, amygdala, and hippocampus [37,38,67]. In contrast, D4 receptors are found in the prefrontal cortex, hippocampus, amygdala, and striatum [52,53,54]. D5 receptors are mainly found in the hippocampus, thalamus, striatum, nucleus accumbens, and amygdala [1,4,5,67].
The endocytic mechanism strictly regulates the number of dopamine D1–D5 receptors on the cell membrane in order to regulate dopaminergic signal transduction. Endocytosis can reduce the number of available receptors on the cell membrane via desensitization, thus decreasing the sensitivity of the cell to dopamine stimulation [68,69]. Endocytosis can also facilitate the recycling of receptors back to the cell membrane through resensitization, thus restoring the responsiveness of the cell to dopamine stimulation [68,69]. Endocytosis can furthermore modulate the signaling output of dopamine receptors by altering their interactions with other proteins, such as G proteins, in different endocytic compartments [68,69,70]. D1-like and D2-like dopamine receptors have different endocytic behaviors and responses to dopamine or drugs. For example, D1-like (D1 and D5) receptors are more resistant to endocytosis than D2-like (D2, D3, and D4) receptors, and they require higher concentrations of dopamine or longer stimulation times to be internalized [68,69]. D2-like receptors are also more sensitive to the effects of β-arrestins, which are proteins that bind to activated G protein-coupled receptors and promote their endocytosis and desensitization [68,69,70]. These data suggest that endocytosis is an important regulator of dopamine receptor signaling and function, and can have implications pertaining to various physiological and pathological processes.

3. Genetic Variants in Dopamine Receptors and Their Impacts on Neuropsychiatric and Movement Disorders

Genetic variants of dopamine receptors, especially single nucleotide polymorphisms (SNPs), have been extensively studied in terms of their association with various neuropsychiatric and neurodegenerative disorders, such as schizophrenia, bipolar disorder, addiction, Alzheimer’s disease, and Parkinson’s disease [71,72]. The effects of these variants may depend on the receptor subtype, the brain region, the disease phenotype, and the interaction with other genes and environmental factors. According to the D1 receptor, an SNP in the DRD1 gene (rs4532) has been linked to cognitive impairment and reduced prefrontal cortex activity in schizophrenia patients [67]. Another SNP (rs686) has been associated with an increased risk of heroin dependence [73,74]. In contrast, several SNPs in the D2 receptor named the DRD2 gene have been implicated in modulating the response to antipsychotic drugs, such as clozapine and risperidone [75]. A common variant (Taq1A) has been related to reduced D2 receptor density in the striatum, and increased susceptibility to addiction and Parkinson’s disease pathogenesis [71].
A functional SNP in the D3 receptor, the DRD3 gene (Ser9Gly), has been shown to influence the affinity of the D3 receptor for dopamine and the efficacy of antipsychotic treatment [76]. This variant has also been associated with Parkinson’s disease, especially in patients with cognitive impairment or psychosis [67]. Furthermore, genetic mutations of dopamine D2 and D3 receptors are associated with the pathogenesis of particular antipsychotics (AP)-induced parkinsonism, and dopamine D1, D2, and D3 receptor mutations affect the AP-induced tardive dyskinesia in patients with schizophrenia, respectively [72].
In the D4 receptor, a variable number tandem repeat (VNTR) polymorphism in the DRD4 gene, which affects the length of the third intracellular loop of the receptor, has been linked to various behavioral and personality traits, such as novelty seeking, impulsivity, and attention-deficit hyperactivity disorder [77]. This polymorphism may also modulate the response to methylphenidate, a dopamine reuptake inhibitor [78]. Concerning the D5 receptor, an SNP in the DRD5 gene has been reported to influence the expression of the D5 receptor in the brain and the susceptibility to schizophrenia [79]. Another SNP (rs1800762) has been associated with cognitive performance and working memory in healthy subjects and schizophrenia patients [71].
These findings suggest that genetic variants of dopamine D1, D2, D3, D4, and D5 receptors significantly affect the function and regulation of dopaminergic neurotransmission, and may contribute to the pathophysiology and treatment of various neurological and psychiatric disorders. Consequently, the functional significance of dopamine receptors spans motor control, reward, mood, attention, and cognitive processes. Therefore, based on the dopamine receptor subtypes and their distribution summarized in this paragraph, the following context from Section 5 will demonstrate the physiological functions of dopamine receptors and their relevance to neurodegenerative diseases categorized by major neuronal nuclei, as well as the pathophysiological significance of dopamine receptors in conditions characterized by dopaminergic dysregulation, such as Parkinson’s disease, schizophrenia, and addiction.

4. Dopamine Receptor Imaging and Disease Implications in Humans

Dopamine receptor imaging is a technique that uses positron emission tomography (PET) or single-photon emission computed tomography (SPECT) to measure the density, distribution, and occupancy of dopamine receptors in the living human brain. Dopamine receptor imaging can provide valuable information on the function and dysfunction of the dopamine system in various neurological and psychiatric disorders, such as Parkinson’s disease, schizophrenia, addiction, and cognitive impairment. Dopamine receptor imaging can also be used to assess the pharmacological effects and optimal dosing of drugs that target dopamine receptors, such as antagonists or partial agonists. Several radiotracers have been developed and validated for dopamine receptor imaging.
[11C]SCH23390 and [18F]fallypride are radioligands that bind to D1 receptors, which are mainly expressed in the striatum and the prefrontal cortex, and which are involved in motor and cognitive functions. [11C]SCH23390 is a selective D1 receptor antagonist [18,19], while [18F]fallypride is a non-selective D2/D3 receptor antagonist that can also bind to D1 receptors with a lower affinity [80,81]. [11C]SCH23390 can be used to measure the D1 receptor density and occupancy in different brain regions, and to investigate the role of D1 receptors in various neurological and psychiatric disorders, such as schizophrenia, Parkinson’s disease, and aging [18,19], which revealed the aging impact on D1 expression and the relation to motor decline in human [19].
Furthermore, [11C]raclopride and [18F]fallypride are non-selective radioligands that bind to both D2 and D3 receptors, and are commonly used to measure the receptor density and occupancy in the striatum and other brain regions. [11C]raclopride is a D2/D3 receptor antagonist with more affinity for D2 receptors [82], while [18F]fallypride is a D2/D3 receptor antagonist with similar affinity for both receptors [81], which visualizes the modified D2/D3 receptor density in a mouse model of Huntington’s disease [80]. These radioligands can be used to study the dopamine system in various neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease, addiction, and cognitive impairment.
In contrast, [11C]PHNO is a radioligand that binds to D3 receptors [50,83]. [11C]PHNO is a selective D3 receptor agonist, and it can be used to measure the D3 receptor density and occupancy in different brain regions, showing the primary distribution in the hypothalamus, substantia nigra, globus pallidus, thalamus, and ventral striatum [50,83], are involved in reward, motivation, and emotion processes, and can be utilized to study the role of D3 receptors in various neuropsychiatric disorders, such as addiction, schizophrenia, and depression [51]. Based on these human clinical findings, the distribution and function of dopamine receptors in each brain nucleus and their involvement in certain diseases will be discussed in the following sections.

5. Physiological Functions of Striatum Dopamine Receptors and Pathogenic Implications

5.1. Impact of Dopamine Receptors in the Dorsal Striatum (Caudate Nucleus and Putamen)

The basal ganglia, another basal nuclei, is an essential neuronal circuit for motor movement, emotion, learning, and cognition. The major components of the basal ganglia include the striatum, consisting of both the dorsal striatum (caudate nucleus and putamen) and the ventral striatum (nucleus accumbens and olfactory tubercle), the globus pallidus, the substantia nigra, and the subthalamic nucleus. The dorsal striatum consists of the putamen, which controls motor functions, and the caudate nucleus, which controls mental functions [84,85,86]. The caudate-putamen is a crucial component of the basal ganglia and involves various essential functions, including motor control, reward processing, and cognitive functions [86,87,88,89,90]. It primarily comprises two subtypes of neurons: the γ-aminobutyric acid (GABAergic) medium-sized spiny neurons (MSNs) in 95% and other interneurons in rodents [85]. Within this dynamic neural nucleus, both D1- and D2-like dopamine receptor subtypes orchestrate indispensable functions, with alterations in their equilibrium implicated in neurodegenerative and neuropsychiatric pathologies, such as Parkinson’s disease, Huntington’s disease, schizophrenia, and addiction [2,36,91,92,93]. Here, we elucidate the physiological significance of D1 and D2 receptors in the striatum, unraveling their distinctive roles in different receptor subtypes.
First, dopamine D1 receptors find predominant expression on the surface of direct pathway medium spiny neurons (dMSNs) [94,95,96]. Their physiological importance spans a spectrum, encompassing the facilitation of movement, reward and reinforcement, cognitive functions, and neuroplasticity. The activation of D1 receptors heightens the excitability of dMSNs, instigating and facilitating the execution of motor functions. These receptors are also integral for the perception of rewarding stimuli, reinforcing behaviors associated with positive outcomes. Striatal D1 receptors contribute to cognitive functions, including working memory, cognitive flexibility, and executive functions [16,94,97,98]. Notably, their stimulation fosters synaptic plasticity, influencing learning and memory processes within the striatum (Table 2).
In contrast, dopamine D2 receptors prominently inhabit the surface of indirect pathway medium spiny neurons (iMSNs) [95,96]. Their physiological role spans the inhibition of movement, the modulation of reward and neurotransmitter release, and the facilitation of motor learning. The activation of D2 receptors inhibits the activity of iMSNs, thereby curtailing the initiation and execution of movement. D2 receptor activation is pivotal in aversion processing and the modulation of responses to negative stimuli, thus contributing a counterbalance to reward-related behaviors. D2 receptors, residing on presynaptic terminals, intricately regulate dopamine release, thereby modulating the overall dopamine concentration in the striatum [26,27,90,108]. Furthermore, D2 receptors play a significant role in motor skill learning and adaptive processes (Table 2).
Dopamine D2 receptors are not only expressed by GABAergic MSNs in the striatum, but also by cholinergic interneurons (CINs), which constitute a small but important population of striatal neurons that release acetylcholine and modulate the activity of MSNs and other striatal cell types [109,110,111,112]. Dopamine D2 receptors in CINs have been shown to regulate the excitability and firing patterns of these neurons, as well as their synaptic interactions with dopaminergic and glutamatergic inputs [110,111]. For instance, the activation of D2 receptors in CINs can reduce their autonomous activity and induce a pause in their firing, which may facilitate the detection and processing of salient stimuli and behavioral responses [111]. Conversely, the blockade of D2 receptors in CINs can increase their firing rate and impair their ability to pause. Moreover, D2 receptors in CINs can modulate the release of acetylcholine in the striatum, which can in turn affect the function of other dopamine receptors, such as D1 and D5 receptors, on MSNs and CINs [111]. Therefore, D2 receptors in CINs may play a crucial role in the fine-tuning of striatal output and dopamine signaling, and may be involved in several aspects of disease. For example, the dysregulation of D2 receptors in CINs may contribute to the pathophysiology of schizophrenia, Parkinson’s disease, and addiction, as these disorders are associated with altered dopamine transmission and impulsive choice behavior [110,111,112].
Maintaining an intricate balance between D1 and D2 pathway activities is imperative for proper motor control and cognitive functions [52,67,84,101,107,113,114,115,116,117]. Perturbations in this delicate equilibrium can lead to motor dysfunction, cognitive impairment, and alterations in reward processing. Imbalances in D1 and D2 signaling are notably associated with a spectrum of neurological and neuropsychiatric disorders, including Parkinson’s disease, schizophrenia, and addiction. These data indicate that the nuanced interplay of D1 and D2 receptors in the striatum regulates motor control, cognitive processes, and the pathophysiology of diverse neurological and neuropsychiatric disorders (Table 2).
Other dopamine receptors, namely D3, D4, and D5 subtypes, exhibit distinct expression patterns and exert intricate influences on brain function [23,38,46,53,54]. D3 receptors, primarily situated in the limbic areas of the striatum, orchestrate emotional responses, motivation, and cognitive functions upon activation. The dysregulation of D3 receptors is strongly linked to addiction, schizophrenia, and mood disorders. In the prefrontal cortex and striatum, D4 receptors play a pivotal role in executive functions, emotional processing, and responses to novelty, with aberrant function being associated with ADHD and specific psychiatric conditions. D5 receptors, widely distributed throughout the brain, contribute significantly to the modulation of both motor activity and cognitive processes. Altered D5 receptor function is implicated in conditions such as schizophrenia and cognitive dysfunction (Table 2). Collectively, these data underscore the pathogenic impact of dopamine receptor subtypes in the striatum on neurological and neuropsychiatric disorders. Imbalances in or the dysregulation of these receptors emphasize the need for targeted therapeutic strategies to restore proper dopaminergic signaling for effective clinical interventions.

5.2. Impact of Dopamine Receptors in the Ventral Striatum (Nucleus Accumbens and Olfactory Tubercle)

The nucleus accumbens and the olfactory tubercle are part of the ventral striatum in the brain [118]. The ventral striatum is involved in processing sensory information, such as olfactory and reward-related information [118,119,120]. The nucleus accumbens, a part of the structure called the striatum, is influenced by neurotransmitters such as dopamine and serotonin. It plays a significant role in behaviors related to pleasure, motivation, decision making, and addiction. On the other hand, the olfactory tubercle is a part of the structure called the olfactory cortex, and receives input from the olfactory epithelium. Apart from olfaction, the olfactory tubercle can integrate sensory information from other senses, such as hearing and vision. This is believed to influence social behavior and emotion.
In the nucleus accumbens, all D1 to D5 receptors are expressed, with D1 and D2 receptors being the most prevalent [1,6,14,36,52,107,117,121,122]. The D1 receptors are mainly localized in the direct pathway of medium spiny neurons, while D2 receptors are primarily found in the indirect pathway of medium spiny neurons. The activation of D1 receptors is believed to be involved in reward, motivation, and learning. Conversely, the activation of D2 receptors is associated with reward, pleasure, and addiction. D3 receptors are predominantly located in the shell of the nucleus accumbens, and are implicated in fear, anxiety, and depression. D4 receptors are mainly found in the core of the nucleus accumbens, and are thought to be involved in psychiatric disorders such as ADHD and schizophrenia. D5 receptors, localized in the shell of the nucleus accumbens and the olfactory tubercle, are believed to play a role in memory and cognition (Table 3).
In contrast, all D1 to D5 receptors are expressed in the olfactory tubercle, with D2 receptors being the most abundant [1,6,14,36,106,121,122]. D2 receptors are primarily localized in the indirect pathway of medium spiny neurons. The activation of D2 receptors is believed to be involved in olfaction, social behavior, and emotion. D1 receptors are mainly found in the direct pathway of medium spiny neurons; D3 receptors are predominantly in large aspiny neurons; D4 receptors are mainly found in medium aspiny neurons; and D5 receptors are primarily localized in the direct pathway of medium spiny neurons. The activation of D1 receptors is considered to be involved in olfaction and learning. The activation of D3 receptors is thought to be associated with olfaction and reward. The activation of D4 receptors is believed to be related to olfaction and attention. The activation of D5 receptors is considered to be involved in olfaction and memory (Table 3). Dopamine D2 receptors in the ventral striatum are not only expressed by GABAergic MSNs, but also by CINs.
Despite the heterogeneous distribution of D1- and D2-like dopamine receptors across the brain, it is noteworthy that these receptors can be expressed on the same type of neurons. Recent findings regarding the modulation of dopamine receptor signaling in striatal neurons reveal pivotal molecular insights, particularly alterations linked to addiction and dyskinesia [15,123,124]. Furthermore, studies comparing the affinities of drugs targeting dopamine receptor subtypes D1, D2, and D3 underscore the potential therapeutic avenues for treating schizophrenia, bipolar disorder, and depression [125]. Notably, investigations into the activation of the D1–D2 receptor complex demonstrate promising outcomes in curbing cocaine-seeking behaviors in animal models, indicating novel signaling pathways involving Gq/phospholipase C (PLC)/protein kinase C (PKC) signaling [126]. In addition to dopamine D1 receptors, the modulation of D2 receptor-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the extracellular signal-regulated kinases (EKR) signaling pathway can alleviate cocaine-induced conditioned place preference (CPP) [127,128,129].
In addition, both MSNs and CINs express dopamine D2 and D3 receptors in the nucleus accumbens [130,131,132]. D2 and D3 receptors have different affinities for dopamine, with D3 receptors having a higher affinity than D2 receptors. Therefore, D3 receptors may be more sensitive to low dopamine levels, while D2 receptors may be more responsive to high dopamine levels. Moreover, D2 and D3 receptors can form heterodimers with each other or with other dopamine receptors [130,131,133,134], such as D1 and D3 receptors [133,134,135]. The co-expression and heterodimerization of D2 receptors and D3 receptors in the nucleus accumbens may distinctly and specifically contribute to the regulation of reward-related behaviors and the development of addiction and other neuropsychiatric disorders [133,134]. For instance, the D2 receptor and D3 receptor in MSNs may differentially modulate the activity and plasticity of the direct and indirect pathways, which have opposite effects on motor output and reward processing. D2 receptors and D3 receptors in CINs may differentially regulate the release of acetylcholine in the nucleus accumbens, which can, in turn, affect the function of other dopamine receptors on MSNs and CINs. The dysregulation of D2 and D3 receptor signaling in the nucleus accumbens may lead to the dysfunction and degeneration of nucleus accumbens neurons and circuits, impairing reward-related learning and decision making [130,131,132,133,134].
Together, these advances underscore the potential of targeted receptor modulation in addressing addiction and neuropsychiatric conditions, offering novel insights and potential therapeutic approaches which target the ventral striatum dopamine receptors.

6. Impact of Dopamine Receptors in the Prefrontal Cortex

The prefrontal cortex represents a pivotal brain region which orchestrates a spectrum of cognitive processes, including executive functions, decision making, emotional regulation, and working memory [136]. Its intricate interplay with the basal ganglia forms the crux of sophisticated neurobehavioral operations, marked by a complex network of parallel loops that underpin diverse physiological functions. Central to this interaction, the prefrontal cortex establishes glutamatergic connections to the striatum, the principal input nucleus of the basal ganglia. Herein, the striatum adeptly integrates a convergence of cortical inputs with dopaminergic innervation stemming from the substantia nigra pars compacta and the ventral tegmental area. Following this integration, the striatum dispatches inhibitory projections to the output structures of the basal ganglia, namely the globus pallidus and the substantia nigra pars reticulata. These output structures govern thalamic activity, modulating the excitatory output that, in a reciprocal loop, is projected back to the prefrontal cortex. This intricate circuitry forms a comprehensive loop involving cortical-striatal-thalamic-cortical pathways, constituting the basis of higher-order cognitive and motor functions. Dopamine receptors in the prefrontal cortex, particularly the D1 and D2 receptor subtypes, play significant roles in these processes.
In detail, dopamine D1 receptors are primarily expressed on the excitatory pyramidal neurons in the prefrontal cortex [121,137,138]. The activation of D1 receptors is associated with improved working memory, cognitive flexibility, and attention. It enhances the strength of excitatory synapses and facilitates the neural circuits responsible for executive functions. The dysfunction of D1 receptors in the prefrontal cortex has been implicated in cognitive disorders such as ADHD and schizophrenia (Table 4).
On the other hand, dopamine D2 receptors in the prefrontal cortex are expressed on both excitatory pyramidal neurons and inhibitory interneurons [8,26,29,140,141,142]. The activation of D2 receptors is generally associated with inhibitory neurotransmission. D2 receptors modulate the balance of excitation and inhibition in the prefrontal cortex, influencing working memory and decision-making processes. Importantly, in the striatum, where D2 receptors are mainly expressed by GABAergic MSNs and CINs, D2 receptor activation preferentially induces G protein signaling, which modulates the activity and plasticity of MSNs, and affects motor and reward-related behaviors [143,144,145,146]. However, in the prefrontal cortex, where D2 receptors are mainly expressed by glutamatergic pyramidal neurons, D2 receptor activation preferentially induces β-arrestin signaling, which modulates the trafficking and stability of D2 receptors, and affects cognitive and emotional functions [144,147,148]. These variations in receptor signaling may underlie differences in physiological functions and contribute to distinct disease conditions. Indeed, the dysregulation of D2 receptor signaling in these brain regions may be involved in the pathophysiology of various neuropsychiatric disorders, such as schizophrenia [149] (Table 4), while the dysregulation of striatal D2 receptors contributes to addiction [145,146] (Table 2).
The D3 receptors, known for their modulation of emotional responses and involvement in motivation and reward circuits, have been implicated in addiction and dependence [38,42,43,46,49]. Their dysregulation is closely associated with mood disorders and addictive behaviors, illuminating their significant role in these conditions. Conversely, the D4 receptors contribute substantially to executive functions, emotional processing, and responses to novelty [53,54,150,151,152]. Their implications in attention disorders, especially attention-deficit hyperactivity disorder (ADHD), and certain psychiatric impairments underscore their role in cognitive and behavioral functions. Additionally, D5 receptors, which modulate cognitive processes and have been tentatively linked to schizophrenia, are associated with cognitive impairments and the development of schizophrenia (Table 4).
These data suggest that dopamine receptors in the prefrontal cortex play a crucial role in regulating cognitive functions, and imbalances or dysfunctions in these receptors can contribute to the pathogenesis of cognitive disorders. Understanding the intricate role of dopamine in the prefrontal cortex is essential for developing targeted therapeutic interventions for cognitive-related conditions.

7. Impact of Dopamine Receptors in the Subthalamic Nucleus

The subthalamic nucleus is a critical part of the basal ganglia circuitry, which is involved in sensory and motor control [153,154,155]. While the presence of dopamine receptors, particularly D1–D5, has been identified, their specific roles and implications in disorders within this specific region are not yet fully elucidated. Parkinson’s disease, characterized by dopaminergic neuron degeneration in the substantia nigra, impacts the basal ganglia circuitry, including the subthalamic nucleus, which has implications for motor symptoms and related dysfunctions [13,102,113,117,156,157,158]. Dopamine receptors in the subthalamic nucleus also play a crucial role in modulating the release of hormones from the hypothalamus, thereby influencing the endocrine system. Dopamine receptors in the hypothalamus have a physiological significance in hormone regulation, temperature regulation, and appetite and weight regulation.
Dopamine D1 receptors in the subthalamic nucleus modulate thalamocortical activity, impacting motor functions, the regulation of neuronal activity, working memory, and cognitive flexibility. Dysregulation in D1 receptors is linked to movement disorders such as Parkinson’s disease, dyskinesia, schizophrenia, and addiction. D2 receptors regulate thalamic output, reward processing, and motor control, and their dysfunction is associated with schizophrenia, Parkinson’s disease, addiction, and depression. D3 receptors mediate thalamic inhibition, motivation, and emotional regulation, and are implicated in schizophrenia, addiction, depression, and anxiety. D4 receptors influence thalamic gating, novelty seeking, and impulsivity, and their dysfunction is implicated in schizophrenia, ADHD, and addiction. D5 receptors enhance thalamocortical transmission, learning, and memory, and their implication extends to schizophrenia, Parkinson’s disease, and Alzheimer’s disease (Table 5).
Furthermore, dopamine receptors in the hypothalamus are also involved in regulating hormone release, including the inhibition of prolactin secretion—a hormone which is crucial for lactation and reproductive functions [31]. Both D1 and D2 receptors may participate in the modulation of hormone release. Dopamine in the hypothalamus also contributes to the regulation of body temperature, influencing thermoregulatory responses. Additionally, dopamine signaling in the hypothalamus is implicated in regulating appetite and body weight, and disruptions in this system may contribute to conditions like obesity. The dysfunction of dopamine receptors in the hypothalamus is linked to the loss of biological homeostasis, potentially leading to disorders of hormone secretion and reproductive system-related conditions. Altered dopamine signaling may also contribute to temperature dysregulation and issues such as hyperthermia or hypothermia. Dysfunction in the dopaminergic system in the hypothalamus has been implicated in disorders related to appetite and weight, including obesity or eating disorders. These data suggest that dopamine receptors in the hypothalamus are crucial for endocrine regulation, metabolism, and related physiological functions.
Therefore, dopamine receptors in the limbic system contribute significantly to motor regulation and hormone secretion. The dysregulation of these receptors is linked to various neuropsychiatric disorders, emphasizing their importance as potential targets for therapeutic interventions. Understanding the nuanced roles of dopamine receptors in these brain regions is crucial for developing targeted treatments for conditions affecting emotional and cognitive functions.

8. Impact of Dopamine Receptors in the Limbic System

8.1. Impact of Dopamine Receptors in the Amygdala

Dopamine receptors in the limbic system, encompassing structures like the amygdala and hippocampus, are integral for emotional processing, memory formation, and reward-related behaviors [3,14,102,107,117,121,122,158,164,165]. The limbic system is a complex network of brain structures that play a crucial role in regulating emotions, memory, and certain autonomic functions. It includes several interconnected regions located in the cerebral cortex and subcortical areas. Pivotal structures within the limbic system include the hippocampus, amygdala, hypothalamus, thalamus, and cingulate gyrus. The limbic system interacts with other brain regions to modulate emotional responses, store and retrieve memories, and regulate physiological processes associated with the stress response. Dysfunction in the limbic system is implicated in various psychiatric and neurological disorders, including mood disorders, anxiety disorders, and memory-related conditions.
The amygdala, with its intricate connections and roles in emotional regulation and fear conditioning, is impacted by dopamine signaling through various receptor subtypes. In the amygdala, both D1 and D2 receptor subtypes are expressed [67,164,166]. The activation of D1 receptors is linked to the modulation of emotional responses, fear learning, and the consolidation of emotional memories. On the other hand, D2 receptor activation in the amygdala is associated with the regulation of anxiety and stress responses [28,38,166]. Dysregulation in dopamine receptor expression or function within the amygdala has been associated with various mood disorders, anxiety disorders, and conditions, involving emotional dysregulation (Table 6).
In contrast, dopamine D3 receptors in the amygdala are implicated in the modulation of emotional responses, motivation, and reward processes, potentially contributing to addiction and dependence. They are suggested to have associations with mood disorders, addictive behaviors, and anxiety disorders. Meanwhile, D4 receptors contribute to emotional processing and play a role in responding to novelty, impacting attention and cognitive tasks. They have been linked to attention-deficit hyperactivity disorder (ADHD), schizophrenia, and depression. Furthermore, D5 receptors modulate emotional responses and are involved in cognitive processes, thus potentially influencing schizophrenia. These receptors have been associated with Alzheimer’s disease, depression, and drug abuse (Table 6).

8.2. Impact of Dopamine Receptors in the Hippocampus

The hippocampus, a critical region for learning and memory, also expresses both D1- and D2-like receptors. Dopamine receptors, particularly the D1 and D2 subtypes, play crucial roles in synaptic plasticity, memory formation, and cognitive functions within the hippocampus [3,5,13,14,21,52,56,102,116,117,162]. Dysregulation or alterations in the expression of these receptors have been associated with various cognitive disorders, memory impairments, and neurodegenerative diseases. D1 receptor activation is involved in long-term potentiation (LTP), a cellular process crucial for memory formation. D2 receptors modulate synaptic plasticity and are involved in memory consolidation. Changes in dopamine receptor function in the hippocampus are associated with cognitive impairments seen in disorders such as Alzheimer’s disease and schizophrenia (Table 7).
In contrast, dopamine D3 receptors in the hippocampus are involved in the modulation of synaptic transmission, and are suggested to play potential roles in hippocampal function. Their dysregulation has been associated with conditions such as schizophrenia, depression, and drug abuse. On the other hand, D4 receptors play a crucial role in modulating neurotransmitter release and receptor sensitivity, which are linked to neuronal development and plasticity. Disruptions in these receptors are implicated in attention-deficit hyperactivity disorder (ADHD), schizophrenia, and depression. Additionally, D5 receptors are responsible for activating the signaling pathways crucial for neuronal plasticity and learning. Dysfunctions in these receptors have been associated with Alzheimer’s disease, depression, and drug abuse (Table 7).
In detail, the hippocampus receives dopaminergic innervation from the following two main sources: the ventral tegmental area (VTA) and the locus coeruleus (LC) [170,171,172]. The VTA provides direct dopaminergic projections to the hippocampus, while the LC provides indirect dopaminergic projections via noradrenergic neurons that co-release dopamine. However, the density and distribution of dopaminergic innervation in the hippocampus are relatively low and heterogeneous when compared to other brain regions, such as the striatum and the prefrontal cortex. Moreover, the dopaminergic innervation shows a dorsoventral gradient, with higher levels in the ventral hippocampus than in the dorsal hippocampus [170,171,172]. The low level of dopamine innervation in the hippocampus may influence the relative roles of the dopamine receptors therein, which include D1, D2, D3, D4, and D5 receptors. These receptors are differentially expressed in the hippocampal subregions and cell types, and mediate the diverse effects impacting synaptic transmission, plasticity, and network activity.
For instance, D1 and D5 receptors are mainly located on the dendritic spines of pyramidal neurons and modulate glutamatergic excitatory inputs, while D2 and D3 receptors are mainly located on the axon terminals of GABAergic interneurons and modulate inhibitory inputs [170,171,172]. D4 receptors are more sparsely expressed, and they have complex effects on both excitatory and inhibitory transmission. The balance and interaction of these receptors may determine the optimal level of dopamine signaling for hippocampal function. The dysregulation of dopamine signaling in the hippocampus may lead to the dysfunction and degeneration of hippocampal neurons and circuits, and may impair hippocampus-dependent memory processes. Several studies have reported reduced levels of dopamine and dopamine receptors in the hippocampus of Alzheimer’s disease patients and animal models, as well as altered dopamine-dependent synaptic plasticity and memory performance [93,173,174,175]. Moreover, some studies have suggested that the modulation of dopamine receptors may have therapeutic potential for Alzheimer’s disease, as it may enhance hippocampal function and attenuate Alzheimer’s disease-related symptoms [93,173,174,175]. These phenomena may contribute to the pathophysiology of Alzheimer’s disease, a neurodegenerative disorder characterized by progressive cognitive decline and memory loss.
Table 7. Major functions of dopamine D1–D5 receptors in the hippocampus and their implication for disorders.
Table 7. Major functions of dopamine D1–D5 receptors in the hippocampus and their implication for disorders.
SubtypesPhysiological FunctionsRelated DiseasesRef.
D1 receptorsModulation of synaptic plasticity, long-term potentiation (LTP), memory formationAlzheimer’s disease, depression, drug abuse[3,5,13,14,34,67,102,116,117,176]
D2 receptorsRegulation of synaptic transmission, modulation of neuronal excitabilityAlzheimer’s disease, depression, drug abuse[14,34,67,116,176]
D3 receptorsModulation of synaptic transmission, potential roles in hippocampal functionSchizophrenia, depression, drug abuse[34,45,67,162,177]
D4 receptorsModulates neurotransmitter release and receptor sensitivity related to neuronal development and plasticityADHD, schizophrenia, depression[34,52,56,67,169]
D5 receptorsActivates signaling pathways required for neuronal plasticity and learningAlzheimer’s disease, depression, drug abuse[20,21,34,67,176]

9. Impact of Dopamine Receptors in the Midbrain

9.1. Impact of Dopamine Receptors in the Substantia Nigra

The physiological significance of dopamine receptors in the substantia nigra (SN) and ventral tegmental area (VTA) is integral to the regulation of movement, reward, and motivation. Both regions are critical components of the dopaminergic system in the brain. The dysregulation of dopamine receptors in these areas is linked to various disorders. In Parkinson’s disease, dopamine-producing neurons are degenerated in the SN, leading to motor impairments [91,101,178,179,180,181,182,183]. Dysfunctions in the VTA and associated reward pathways are implicated in addiction and mood disorders [184,185,186,187].
The substantia nigra, particularly its dopamine-abundant areas, plays a crucial role in motor control, reward mechanisms, and behavioral responses [15,67]. In the intricate orchestration of neurotransmission within the mesencephalic substantia nigra, dopamine D1-like and D2-like receptors play pivotal roles, particularly in the modulation of GABA release to the globus pallidus via the striatum. Dopamine receptors, especially the D1 and D2 subtypes, are integral in regulating motor function and reward processing within this brain region. Dysregulation or alterations in the expression of these receptors are strongly associated with movement disorders, including Parkinson’s disease, and could potentially contribute to other neuropsychiatric conditions.
In the SN, particularly the pars compacta, dopamine-producing neurons play a central role in controlling voluntary movement. In Parkinson’s disease and dopa-responsive dystonia, particularly tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis, is reduced; therefore, the strict regulation of dopamine receptors is crucial [182,188]. The activation of D1 receptors in the nigrostriatal pathway, particularly on the surface of the dMSNs, facilitates the initiation and execution of movement. These receptors enhance the excitability of GABAergic dMSNs to enhance GABA release to the internal segment of globus pallidus (GPi), resulting in the promotion of motor function [189,190,191,192,193].
Simultaneously, D2 receptors, predominantly expressed in the indirect pathway medium spiny neurons (iMSNs), exert inhibitory control over GABA release to the external segment of globus pallidus (GPe), which modulates the GPi through the subthalamic nucleus [189,190,191,192,193]. The interplay between the D1 and D2 receptor-mediated modulation of GABAergic transmission intricately regulates the output of the substantia nigra, influencing downstream motor circuits. The dysregulation or degeneration of dopamine-producing neurons in the pars compacta, leading to alterations in D1 and D2 receptor activation and GABA release, is a hallmark of Parkinson’s disease. This results in motor symptoms such as tremors, rigidity, and bradykinesia (Table 8).
Dopamine D3 receptors in SN play a role in modulating emotional responses and regulating cognitive functions, potentially having implications for movement disorders. On the other hand, D4 receptors contribute to executive functions and are involved in responding to novelty. Dysfunctions in these receptors are associated with Parkinson’s disease and motor impairments. Additionally, D5 receptors are responsible for modulating motor activity and regulating cognitive functions. Aberrations in these receptors have been linked to Parkinson’s disease and motor impairments (Table 8).
Parkinsonism is a typical phenotype of substantia nigra dysfunction. Parkinson’s disease is characterized by a significant reduction in the levels of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis [196,197,198,199,200]. This reduction leads to a diminished capacity for dopamine synthesis, necessitating the precise regulation of dopamine receptors [197,198,200]. Reduced dopamine production in parkinsonism results in the reduction of D1 receptor activation. This leads to a decrease in the excitability of dMSNs and a subsequent reduction in GABA release to GPi. The impaired excitatory input to the GPi contributes to motor symptoms like tremors, rigidity, and bradykinesia [201,202,203]. In contrast, D2 receptors exert inhibitory control over GABA release to GPe. The modulation of GABAergic transmission by D2 receptors is crucial for the delicate balance between the direct and indirect pathways [10,204]. In parkinsonism, alterations in D2 receptor activation disrupt this balance, contributing to the overall motor dysfunction observed in the disease. The intricate interplay between the D1 and D2 receptor-mediated modulation of GABAergic transmission intricately regulates the output of the substantia nigra, influencing downstream motor circuits. Furthermore, the compensatory enhancement of TH phosphorylation and dopamine D1 receptor expression alleviates motor dysfunction in order to mitigate the severity of hypokinesia [205]. These data imply that the dysregulation or degeneration of dopamine-producing neurons in the pars compacta leads to alterations in D1 and D2 receptor activation and GABA release, which is a hallmark of Parkinson’s disease.

9.2. Impact of Dopamine Receptors in the Ventral Tegmental Area

On the other hand, VTA is a crucial brain region, containing dopaminergic neurons that project to various areas of the brain, including the nucleus accumbens and prefrontal cortex [185,206,207,208,209]. The physiological significance of dopamine receptors in the VTA is associated with regulating reward, motivation, reinforcement, and cognitive functions. D1 receptors in the VTA play a key role in the reward pathway. The activation of these receptors is involved in the experience of pleasure and the reinforcement of behaviors associated with positive outcomes. They contribute to the motivation one feels to seek rewards. The dysregulation of D1 receptor signaling in the VTA is implicated in reward processing and motivation disorders. This dysfunction is associated with conditions like addiction, where there is an aberrant reinforcement of drug-seeking behavior (Table 9).
In contrast, D2 receptors in the VTA are involved in modulating the response to rewarding and aversive stimuli. Their activation can inhibit dopamine release in target areas, thus contributing to the regulation of reward-related behaviors. Imbalances in D2 receptor function in the VTA are associated with psychiatric conditions, including schizophrenia. Altered dopamine release and disrupted reward processing contribute to the symptomatology of these disorders. The activation of D2 receptors in the nucleus accumbens, which is the projection site of VTA dopaminergic neurons, is associated with the hedonic aspects of reward-related behaviors (Table 9).
Dopamine D3 receptors in VTA exert an influence on motivation and reward processing, potentially playing a role in drug addiction and dependence. Dysfunction in these receptors is implicated in addiction and reward-related disorders. D4 receptors are involved in regulating dopamine pathways, and may have a role in motivation, potentially contributing to motivation and reward-related disorders, as well as depression. Additionally, D5 receptors modulate neurotransmission, impacting motor functions and cognitive processes. Dysfunctions in these receptors are associated with addiction and cognitive impairments, along with depression (Table 9).
These data suggest that the physiological significance of dopamine receptors in the SN lies in their role to regulate motor function via the intricate balance of D1 and D2 receptor-mediated pathways. The pathogenic impact involves disruptions in this balance, leading to movement disorders like Parkinson’s disease. In contrast, the physiological significance of dopamine receptors in the VTA lies in their central role in the brain’s reward system. The pathogenic impact involves disruptions in reward processing, motivation, and reinforcement, contributing to the development of neuropsychiatric disorders.

10. Dopamine Receptors as Drug Targets

10.1. Dopamine D1-like Receptors as Therapeutic Targets

This review highlighted that the dopamine receptors in various brain nuclei are involved in diverse neuropsychiatric disorders, such as depression, schizophrenia, Parkinson’s disease, and drug addiction. Therefore, they have been considered as potential therapeutic targets for the development of novel drugs. However, the complexity and diversity of dopamine receptor signaling, and pharmacology pose significant challenges for designing selective and effective ligands. As mentioned above, dopamine D1 receptors are mainly expressed in the striatum, stimulating the direct pathway and facilitating movement. They are also expressed in the prefrontal cortex, enhancing cognitive functions such as working memory, attention, and decision making. Because of the wide variety of functions and distributions, the development of clinically effective D1 receptor agonists has been challenging due to the lack of selectivity, bioavailability, and safety of the available compounds.
The exploration of D1/D5 receptor-selective partial agonists shows promise in providing sustained, predictable motor control, while reducing the risk of complications, presenting a potential shift in the classification of dopamine agonists based on their receptor selectivity [214]. High intrinsic activity D1 agonists could offer significant symptomatic relief, even in severe stages of the disease, potentially improving the quality of life for late-stage Parkinson’s patients [215]. In recent years, several novel non-catecholamine D1 receptor agonists have been discovered, which demonstrate improved pharmacological properties and therapeutic potential. Non-catecholamine D1/D5 receptor agonists can dissociate Gs protein signaling from β-arrestin recruitment, and may be useful for treating motor impairment in Parkinson’s disease and cognitive impairment in neuropsychiatric disorders [15,216]. For example, the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one] demonstrated significant allosteric effects in human D1 receptors, inducing a leftward shift in the cAMP response to dopamine [217]. DETQ increased locomotor activity in a dose-dependent manner in a knock-in mouse model expressing human D1 receptors [217]. In addition, PF-06649751, also known as tavapadon, is a partial agonist of the dopamine D1/D5 receptor [218,219,220]. PF-06649751 has been shown to improve motor function in Parkinson’s disease [218,219,220]. PF-06649751 has a novel non-catechol structure, which may make it more selective and stable than other dopamine agonists [220]. PF-06412562 is also a partial agonist of dopamine D1 and D5 receptors, which are involved in motor functions [221,222,223]. PF-06412562 has been shown to improve motor deficits in Parkinson’s disease with no serious adverse events, severe adverse events, or adverse events, although it did not improve cognitive function or motivation/reward processing [221]. Although clinical trials are challenging due to inadequate therapeutic efficacy and side effects [179], dopamine D1-like receptors remain a potential therapeutic target.

10.2. Dopamine D2-like Receptors as Therapeutic Targets

In contrast, dopamine D2 receptors are widely distributed in the brain, where they mediate diverse functions, such as reward processing, reinforcement learning, and motor coordination, as described above. While striatal D2 receptors were significantly decreased in PD patients when compared to a healthy control group and patients with Alzheimer’s disease, combined densities of striatal D1 and D3 receptors showed better correlations with clinical manifestations of Parkinson’s disease, suggesting potential implications for diagnosis, treatment, and prognosis, especially in elderly patients with low D2 receptors expression [224]. The majority of antipsychotic drugs target D2 receptors, as they block the excessive dopamine transmission that is associated with psychotic symptoms. However, these drugs also cause adverse effects, such as extrapyramidal symptoms, weight gain, and metabolic syndrome, due to their lack of specificity and their blockade of D2 receptors in other brain regions. Therefore, there is a need for more selective and efficacious D2 receptor modulators that can restore the optimal balance of dopamine signaling in different brain circuits.
Biased D2 receptor agonists can preferentially activate Gi protein or β-arrestin pathways, and may exert different effects on reward and aversion [34]. Moreover, allosteric modulators can modulate the affinity and efficacy of orthosteric ligands, and may provide more fine-tuned control over dopamine receptor signaling [225]. One approach is to develop D2 receptor partial agonists, which have lower intrinsic activity than full agonists, and can act as antagonists in the presence of high dopamine levels or agonists in the presence of low dopamine levels. Examples of D2 receptor partial agonists are aripiprazole and brexpiprazole, which are approved for the treatment of schizophrenia, bipolar disorder, and major depressive disorder [226,227]. Another approach is to develop D2 receptor allosteric modulators, which bind to a distinct site from the orthosteric site and enhance or inhibit the binding and efficacy of the endogenous ligand or other drugs. For instance, PAOPA is a positive allosteric modulator of D2 receptors, which increases the affinity and potency of dopamine and D2 receptor agonists, and reverses the motor and cognitive impairments induced by D2 receptor antagonists [228,229]. In addition, a novel modulator of dopamine D2 receptors for the treatment of drug dependence exerts its therapeutic effect by suppressing the interaction between D2L receptors and FABP3 [127]. These novel compounds represent promising candidates for future drug development, and may pave the way for more personalized and precise treatments for dopamine receptor-related disorders.

11. Conclusions

In conclusion, this review article provided an overview of the brain distribution and physiological functions of dopamine D1–D5 receptors, emphasizing their involvement in disorders arising from dysfunction, with a particular focus on representative brain nuclei. Predominantly, by spotlighting the striatum, encompassing the caudate nucleus, putamen, nucleus accumbens, and olfactory tubercle, as well as projection networks including the prefrontal cortex, subthalamic nucleus, amygdala, hippocampus, substantia nigra, and ventral tegmental area, this review discussed nuclei-specific expression patterns of dopamine D1–D5 receptors, their physiological functions, and potential disorders associated with their dysfunction and mutations. The biological functions of dopamine receptors extend beyond motor function, encompassing cognitive memory, motivation, and drug addiction. Understanding the biology of dopamine receptors not only advances the fundamental knowledge of the central nervous system, but also provides promising clues for therapeutic interventions. With the global aging society, exploring dopamine receptors as potential therapeutic targets has become crucial. Progress in therapeutic development, coupled with a nuanced understanding of these receptors, opens pathways to innovative strategies for treating conditions like Parkinson’s disease and schizophrenia, as well as Alzheimer’s disease and drug dependency. Continued research unraveling the molecular complexity of dopamine receptors holds promise for the discovery of new therapies, and ultimately contributes to enhancing neurological health in an aging society.

Author Contributions

Conceptualization, I.K.; writing—original draft preparation, I.K.; writing—review and editing, D.I.F. and K.F.; funding acquisition, I.K., D.I.F. and K.F. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded in part by the Japan Society for the Promotion of Science, KAKENHI (22K06644), Takeda Science Foundation to I.K., and Australian National Health and Medical Research Council, The Michael J. Fox Foundation for Parkinson’s Disease Research for D.I.F.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Jackson, D.M.; Westlind-Danielsson, A. Dopamine receptors: Molecular biology, biochemistry and behavioural aspects. Pharmacol. Ther. 1994, 64, 291–370. [Google Scholar] [CrossRef] [PubMed]
  2. Wang, H.Y.; Undie, A.S.; Friedman, E. Evidence for the coupling of Gq protein to D1-like dopamine sites in rat striatum: Possible role in dopamine-mediated inositol phosphate formation. Mol. Pharmacol. 1995, 48, 988–994. [Google Scholar] [PubMed]
  3. Jin, L.Q.; Wang, H.Y.; Friedman, E. Stimulated D1 dopamine receptors couple to multiple Gα proteins in different brain regions. J. Neurochem. 2001, 78, 981–990. [Google Scholar] [CrossRef] [PubMed]
  4. Karlsson, R.M.; Hefner, K.R.; Sibley, D.R.; Holmes, A. Comparison of dopamine D1 and D5 receptor knockout mice for cocaine locomotor sensitization. Psychopharmacology 2008, 200, 117–127. [Google Scholar] [CrossRef] [PubMed]
  5. Bergson, C.; Mrzljak, L.; Smiley, J.F.; Pappy, M.; Levenson, R.; Goldman-Rakic, P.S. Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain. J. Neurosci. 1995, 15, 7821–7836. [Google Scholar] [CrossRef] [PubMed]
  6. Boyson, S.J.; McGonigle, P.; Molinoff, P.B. Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain. J. Neurosci. 1986, 6, 3177–3188. [Google Scholar] [CrossRef] [PubMed]
  7. Bunzow, J.R.; Van Tol, H.H.; Grandy, D.K.; Albert, P.; Salon, J.; Christie, M.; Machida, C.A.; Neve, K.A.; Civelli, O. Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 1988, 336, 783–787. [Google Scholar] [CrossRef] [PubMed]
  8. Weiner, D.M.; Brann, M.R. The distribution of a dopamine D2 receptor mRNA in rat brain. FEBS Lett. 1989, 253, 207–213. [Google Scholar] [CrossRef] [PubMed]
  9. Levey, A.I.; Hersch, S.M.; Rye, D.B.; Sunahara, R.K.; Niznik, H.B.; Kitt, C.A.; Price, D.L.; Maggio, R.; Brann, M.R.; Ciliax, B.J. Localization of D1 and D2 dopamine receptors in brain with subtype-specific antibodies. Proc. Natl. Acad. Sci. USA 1993, 90, 8861–8865. [Google Scholar] [CrossRef]
  10. Cho, H.S.; Baek, D.J.; Baek, S.S. Effect of exercise on hyperactivity, impulsivity and dopamine D2 receptor expression in the substantia nigra and striatum of spontaneous hypertensive rats. J. Exerc. Nutr. Biochem. 2014, 18, 379–384. [Google Scholar] [CrossRef]
  11. Undieh, A.S. Pharmacology of signaling induced by dopamine D1-like receptor activation. Pharmacol. Ther. 2010, 128, 37–60. [Google Scholar] [CrossRef]
  12. Channer, B.; Matt, S.M.; Nickoloff-Bybel, E.A.; Pappa, V.; Agarwal, Y.; Wickman, J.; Gaskill, P.J. Dopamine, Immunity, and Disease. Pharmacol. Rev. 2023, 75, 62–158. [Google Scholar] [CrossRef]
  13. Savasta, M.; Dubois, A.; Scatton, B. Autoradiographic localization of D1 dopamine receptors in the rat brain with [3H]SCH 23390. Brain Res. 1986, 375, 291–301. [Google Scholar] [CrossRef]
  14. Wamsley, J.K.; Gehlert, D.R.; Filloux, F.M.; Dawson, T.M. Comparison of the distribution of D-1 and D-2 dopamine receptors in the rat brain. J. Chem. Neuroanat. 1989, 2, 119–137. [Google Scholar] [PubMed]
  15. Jones-Tabah, J.; Mohammad, H.; Paulus, E.G.; Clarke, P.B.S.; Hebert, T.E. The Signaling and Pharmacology of the Dopamine D1 Receptor. Front. Cell. Neurosci. 2021, 15, 806618. [Google Scholar] [CrossRef]
  16. Goutier, W.; O’Connor, J.J.; Lowry, J.P.; McCreary, A.C. The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat. Eur. Neuropsychopharmacol. 2015, 25, 933–943. [Google Scholar] [CrossRef] [PubMed]
  17. Bahi, A.; Dreyer, J.L. Involvement of nucleus accumbens dopamine D1 receptors in ethanol drinking, ethanol-induced conditioned place preference, and ethanol-induced psychomotor sensitization in mice. Psychopharmacology 2012, 222, 141–153. [Google Scholar] [CrossRef] [PubMed]
  18. Stenkrona, P.; Matheson, G.J.; Cervenka, S.; Sigray, P.P.; Halldin, C.; Farde, L. [11C]SCH23390 binding to the D1-dopamine receptor in the human brain-a comparison of manual and automated methods for image analysis. EJNMMI Res. 2018, 8, 74. [Google Scholar] [CrossRef]
  19. Suhara, T.; Fukuda, H.; Inoue, O.; Itoh, T.; Suzuki, K.; Yamasaki, T.; Tateno, Y. Age-related changes in human D1 dopamine receptors measured by positron emission tomography. Psychopharmacology 1991, 103, 41–45. [Google Scholar] [CrossRef]
  20. Khan, Z.U.; Gutierrez, A.; Martin, R.; Penafiel, A.; Rivera, A.; de la Calle, A. Dopamine D5 receptors of rat and human brain. Neuroscience 2000, 100, 689–699. [Google Scholar] [CrossRef]
  21. Kramar, C.P.; Barbano, M.F.; Medina, J.H. Dopamine D1/D5 receptors in the dorsal hippocampus are required for the acquisition and expression of a single trial cocaine-associated memory. Neurobiol. Learn. Mem. 2014, 116, 172–180. [Google Scholar] [CrossRef] [PubMed]
  22. Hansen, N.; Manahan-Vaughan, D. Dopamine D1/D5 receptors mediate informational saliency that promotes persistent hippocampal long-term plasticity. Cereb. Cortex 2014, 24, 845–858. [Google Scholar] [CrossRef] [PubMed]
  23. Castello, J.; Cortes, M.; Malave, L.; Kottmann, A.; Sibley, D.R.; Friedman, E.; Rebholz, H. The Dopamine D5 receptor contributes to activation of cholinergic interneurons during L-DOPA induced dyskinesia. Sci. Rep. 2020, 10, 2542. [Google Scholar] [CrossRef] [PubMed]
  24. Meador-Woodruff, J.H.; Mansour, A.A.E. Bennett Award paper. Expression of the dopamine D2 receptor gene in brain. Biol. Psychiatry 1991, 30, 985–1007. [Google Scholar] [CrossRef] [PubMed]
  25. Takeuchi, Y.; Fukunaga, K. Dopamine D2 receptor activates extracellular signal-regulated kinase through the specific region in the third cytoplasmic loop. J. Neurochem. 2004, 89, 1498–1507. [Google Scholar] [CrossRef] [PubMed]
  26. van der Weide, J.; Camps, M.; Horn, A.S.; Palacios, J.M. Autoradiographic localization of dopamine D2 receptors in the rat brain using the new agonist [3H]N-0437. Neurosci. Lett. 1987, 83, 259–263. [Google Scholar] [CrossRef]
  27. Charuchinda, C.; Supavilai, P.; Karobath, M.; Palacios, J.M. Dopamine D2 receptors in the rat brain: Autoradiographic visualization using a high-affinity selective agonist ligand. J. Neurosci. 1987, 7, 1352–1360. [Google Scholar] [CrossRef] [PubMed]
  28. De Keyser, J.; De Backer, J.P.; Ebinger, G.; Vauquelin, G. Regional distribution of the dopamine D2 receptors in the mesotelencephalic dopamine neuron system of human brain. J. Neurol. Sci. 1985, 71, 119–127. [Google Scholar] [CrossRef] [PubMed]
  29. Luabeya, M.K.; Maloteaux, J.M.; Laduron, P.M. Regional and cortical laminar distributions of serotonin S2, benzodiazepine, muscarinic, and dopamine D2 receptors in human brain. J. Neurochem. 1984, 43, 1068–1071. [Google Scholar] [CrossRef] [PubMed]
  30. Kohler, C.; Radesater, A.C. Autoradiographic visualization of dopamine D-2 receptors in the monkey brain using the selective benzamide drug [3H]raclopride. Neurosci. Lett. 1986, 66, 85–90. [Google Scholar] [CrossRef]
  31. Missale, C.; Nash, S.R.; Robinson, S.W.; Jaber, M.; Caron, M.G. Dopamine receptors: From structure to function. Physiol. Rev. 1998, 78, 189–225. [Google Scholar] [CrossRef]
  32. Schmitz, Y.; Benoit-Marand, M.; Gonon, F.; Sulzer, D. Presynaptic regulation of dopaminergic neurotransmission. J. Neurochem. 2003, 87, 273–289. [Google Scholar] [CrossRef]
  33. De Mei, C.; Ramos, M.; Iitaka, C.; Borrelli, E. Getting specialized: Presynaptic and postsynaptic dopamine D2 receptors. Curr. Opin. Pharmacol. 2009, 9, 53–58. [Google Scholar] [CrossRef] [PubMed]
  34. Beaulieu, J.M.; Gainetdinov, R.R. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol. Rev. 2011, 63, 182–217. [Google Scholar] [CrossRef]
  35. Le Coniat, M.; Sokoloff, P.; Hillion, J.; Martres, M.P.; Giros, B.; Pilon, C.; Schwartz, J.C.; Berger, R. Chromosomal localization of the human D3 dopamine receptor gene. Hum. Genet. 1991, 87, 618–620. [Google Scholar] [CrossRef] [PubMed]
  36. Meador-Woodruff, J.H.; Damask, S.P.; Wang, J.; Haroutunian, V.; Davis, K.L.; Watson, S.J. Dopamine receptor mRNA expression in human striatum and neocortex. Neuropsychopharmacology 1996, 15, 17–29. [Google Scholar] [CrossRef]
  37. Shafer, R.A.; Levant, B. The D3 dopamine receptor in cellular and organismal function. Psychopharmacology 1998, 135, 1–16. [Google Scholar] [CrossRef]
  38. Gurevich, E.V.; Joyce, J.N. Distribution of dopamine D3 receptor expressing neurons in the human forebrain: Comparison with D2 receptor expressing neurons. Neuropsychopharmacology 1999, 20, 60–80. [Google Scholar] [CrossRef] [PubMed]
  39. Black, K.J.; Hershey, T.; Koller, J.M.; Videen, T.O.; Mintun, M.A.; Price, J.L.; Perlmutter, J.S. A possible substrate for dopamine-related changes in mood and behavior: Prefrontal and limbic effects of a D3-preferring dopamine agonist. Proc. Natl. Acad. Sci. USA 2002, 99, 17113–17118. [Google Scholar] [CrossRef]
  40. Beninger, R.J.; Banasikowski, T.J. Dopaminergic mechanism of reward-related incentive learning: Focus on the dopamine D3 receptor. Neurotox. Res. 2008, 14, 57–70. [Google Scholar] [CrossRef]
  41. Khaled, M.A.; Pushparaj, A.; Di Ciano, P.; Diaz, J.; Le Foll, B. Dopamine D3 receptors in the basolateral amygdala and the lateral habenula modulate cue-induced reinstatement of nicotine seeking. Neuropsychopharmacology 2014, 39, 3049–3058. [Google Scholar] [CrossRef] [PubMed]
  42. Kiss, B.; Laszlovszky, I.; Krámos, B.; Visegrády, A.; Bobok, A.; Lévay, G.; Lendvai, B.; Román, V. Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders. Biomolecules 2021, 11, 104. [Google Scholar] [CrossRef] [PubMed]
  43. Kong, H.; Kuang, W.; Li, S.; Xu, M. Activation of dopamine D3 receptors inhibits reward-related learning induced by cocaine. Neuroscience 2011, 176, 152–161. [Google Scholar] [CrossRef] [PubMed]
  44. Zhang, L.; Lou, D.; Jiao, H.; Zhang, D.; Wang, X.; Xia, Y.; Zhang, J.; Xu, M. Cocaine-induced intracellular signaling and gene expression are oppositely regulated by the dopamine D1 and D3 receptors. J. Neurosci. 2004, 24, 3344–3354. [Google Scholar] [CrossRef] [PubMed]
  45. Xing, B.; Kong, H.; Meng, X.; Wei, S.G.; Xu, M.; Li, S.B. Dopamine D1 but not D3 receptor is critical for spatial learning and related signaling in the hippocampus. Neuroscience 2010, 169, 1511–1519. [Google Scholar] [CrossRef]
  46. Andreoli, M.; Tessari, M.; Pilla, M.; Valerio, E.; Hagan, J.J.; Heidbreder, C.A. Selective antagonism at dopamine D3 receptors prevents nicotine-triggered relapse to nicotine-seeking behavior. Neuropsychopharmacology 2003, 28, 1272–1280. [Google Scholar] [CrossRef] [PubMed]
  47. Kim, K.M.; Valenzano, K.J.; Robinson, S.R.; Yao, W.D.; Barak, L.S.; Caron, M.G. Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J. Biol. Chem. 2001, 276, 37409–37414. [Google Scholar] [CrossRef] [PubMed]
  48. Shioda, N.; Takeuchi, Y.; Fukunaga, K. Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: Proteins interacting with the third cytoplasmic loop of dopamine D2 and D3 receptors. J. Pharmacol. Sci. 2010, 114, 25–31. [Google Scholar] [CrossRef] [PubMed]
  49. Du, F.; Li, R.; Huang, Y.; Li, X.; Le, W. Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons. Eur. J. Neurosci. 2005, 22, 2422–2430. [Google Scholar] [CrossRef]
  50. Searle, G.; Beaver, J.D.; Comley, R.A.; Bani, M.; Tziortzi, A.; Slifstein, M.; Mugnaini, M.; Griffante, C.; Wilson, A.A.; Merlo-Pich, E.; et al. Imaging dopamine D3 receptors in the human brain with positron emission tomography, [11C]PHNO, and a selective D3 receptor antagonist. Biol. Psychiatry 2010, 68, 392–399. [Google Scholar] [CrossRef]
  51. Koohsari, S.; Yang, Y.; Matuskey, D. D3 Receptors and PET Imaging. In Therapeutic Applications of Dopamine D3 Receptor Function: New Insight after 30 Years of Research; Boileau, I., Collo, G., Eds.; Springer International Publishing: Cham, Switzerland, 2023; pp. 251–275. [Google Scholar]
  52. Defagot, M.C.; Malchiodi, E.L.; Villar, M.J.; Antonelli, M.C. Distribution of D4 dopamine receptor in rat brain with sequence-specific antibodies. Brain Res. Mol. Brain Res. 1997, 45, 1–12. [Google Scholar] [CrossRef] [PubMed]
  53. Wedzony, K.; Chocyk, A.; Maćkowiak, M.; Fijał, K.; Czyrak, A. Cortical localization of dopamine D4 receptors in the rat brain—Immunocytochemical study. J. Physiol. Pharmacol. 2000, 51, 205–221. [Google Scholar]
  54. Rivera, A.; Cuéllar, B.; Girón, F.J.; Grandy, D.K.; de la Calle, A.; Moratalla, R. Dopamine D4 receptors are heterogeneously distributed in the striosomes/matrix compartments of the striatum. J. Neurochem. 2002, 80, 219–229. [Google Scholar] [CrossRef] [PubMed]
  55. Rondou, P.; Haegeman, G.; Van Craenenbroeck, K. The dopamine D4 receptor: Biochemical and signalling properties. Cell. Mol. Life Sci. 2010, 67, 1971–1986. [Google Scholar] [CrossRef] [PubMed]
  56. Guo, F.; Zhao, J.; Zhao, D.; Wang, J.; Wang, X.; Feng, Z.; Vreugdenhil, M.; Lu, C. Dopamine D4 receptor activation restores CA1 LTP in hippocampal slices from aged mice. Aging Cell 2017, 16, 1323–1333. [Google Scholar] [CrossRef] [PubMed]
  57. Xiang, L.; Szebeni, K.; Szebeni, A.; Klimek, V.; Stockmeier, C.A.; Karolewicz, B.; Kalbfleisch, J.; Ordway, G.A. Dopamine receptor gene expression in human amygdaloid nuclei: Elevated D4 receptor mRNA in major depression. Brain Res. 2008, 1207, 214–224. [Google Scholar] [CrossRef] [PubMed]
  58. Hyde, T.M.; Knable, M.B.; Murray, A.M. Distribution of dopamine D1-D4 receptor subtypes in human dorsal vagal complex. Synapse 1996, 24, 224–232. [Google Scholar] [CrossRef]
  59. Khan, Z.U.; Mrzljak, L.; Gutierrez, A.; de la Calle, A.; Goldman-Rakic, P.S. Prominence of the dopamine D2 short isoform in dopaminergic pathways. Proc. Natl. Acad. Sci. USA 1998, 95, 7731–7736. [Google Scholar] [CrossRef] [PubMed]
  60. Wang, Y.; Xu, R.; Sasaoka, T.; Tonegawa, S.; Kung, M.P.; Sankoorikal, E.B. Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. J. Neurosci. 2000, 20, 8305–8314. [Google Scholar] [CrossRef]
  61. Weissenrieder, J.S.; Neighbors, J.D.; Mailman, R.B.; Hohl, R.J. Cancer and the Dopamine D2 Receptor: A Pharmacological Perspective. J. Pharmacol. Exp. Ther. 2019, 370, 111–126. [Google Scholar] [CrossRef]
  62. Kawahata, I.; Sekimori, T.; Wang, H.; Wang, Y.; Sasaoka, T.; Bousset, L.; Melki, R.; Mizobata, T.; Kawata, Y.; Fukunaga, K. Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons. Biomedicines 2021, 9, 49. [Google Scholar] [CrossRef]
  63. Ford, C.P. The role of D2-autoreceptors in regulating dopamine neuron activity and transmission. Neuroscience 2014, 282, 13–22. [Google Scholar] [CrossRef]
  64. Gantz, S.C.; Robinson, B.G.; Buck, D.C.; Bunzow, J.R.; Neve, R.L.; Williams, J.T.; Neve, K.A. Distinct regulation of dopamine D2S and D2L autoreceptor signaling by calcium. eLife 2015, 4, e09358. [Google Scholar] [CrossRef]
  65. Jomphe, C.; Tiberi, M.; Trudeau, L.E. Expression of D2 receptor isoforms in cultured neurons reveals equipotent autoreceptor function. Neuropharmacology 2006, 50, 595–605. [Google Scholar] [CrossRef] [PubMed]
  66. Takeuchi, Y.; Fukunaga, K. Differential subcellular localization of two dopamine D2 receptor isoforms in transfected NG108-15 cells. J. Neurochem. 2003, 85, 1064–1074. [Google Scholar] [CrossRef] [PubMed]
  67. Martel, J.C.; Gatti McArthur, S. Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia. Front. Pharmacol. 2020, 11, 1003. [Google Scholar] [CrossRef]
  68. Andersson, E.R. The role of endocytosis in activating and regulating signal transduction. Cell. Mol. Life Sci. 2012, 69, 1755–1771. [Google Scholar] [CrossRef] [PubMed]
  69. Ehrlich, A.T.; Couvineau, P.; Schamiloglu, S.; Wojcik, S.; Da Fonte, D.; Mezni, A.; von Zastrow, M.; Bender, K.J.; Bouvier, M.; Kieffer, B.L. Visualization of real-time receptor endocytosis in dopamine neurons enabled by NTSR1-Venus knock-in mice. Front. Cell. Neurosci. 2022, 16, 1076599. [Google Scholar] [CrossRef] [PubMed]
  70. Kawahata, I.; Fukunaga, K. Endocytosis of dopamine receptor: Signaling in brain. Prog. Mol. Biol. Transl. Sci. 2023, 196, 99–111. [Google Scholar] [CrossRef]
  71. Magistrelli, L.; Ferrari, M.; Furgiuele, A.; Milner, A.V.; Contaldi, E.; Comi, C.; Cosentino, M.; Marino, F. Polymorphisms of Dopamine Receptor Genes and Parkinson’s Disease: Clinical Relevance and Future Perspectives. Int. J. Mol. Sci. 2021, 22, 3781. [Google Scholar] [CrossRef]
  72. Vaiman, E.E.; Shnayder, N.A.; Novitsky, M.A.; Dobrodeeva, V.S.; Goncharova, P.S.; Bochanova, E.N.; Sapronova, M.R.; Popova, T.E.; Tappakhov, A.A.; Nasyrova, R.F. Candidate Genes Encoding Dopamine Receptors as Predictors of the Risk of Antipsychotic-Induced Parkinsonism and Tardive Dyskinesia in Schizophrenic Patients. Biomedicines 2021, 9, 879. [Google Scholar] [CrossRef] [PubMed]
  73. Paudel, P.; Park, S.E.; Seong, S.H.; Jung, H.A.; Choi, J.S. Novel Diels-Alder Type Adducts from Morus alba Root Bark Targeting Human Monoamine Oxidase and Dopaminergic Receptors for the Management of Neurodegenerative Diseases. Int. J. Mol. Sci. 2019, 20, 6232. [Google Scholar] [CrossRef] [PubMed]
  74. Acharya, S.; Kim, K.M. Roles of the Functional Interaction between Brain Cholinergic and Dopaminergic Systems in the Pathogenesis and Treatment of Schizophrenia and Parkinson’s Disease. Int. J. Mol. Sci. 2021, 22, 4299. [Google Scholar] [CrossRef] [PubMed]
  75. Taheri, N.; Pirboveiri, R.; Sayyah, M.; Bijanzadeh, M.; Ghandil, P. Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia. BMC Psychiatry 2023, 23, 781. [Google Scholar] [CrossRef] [PubMed]
  76. Liu, C.; Xu, X.; Liu, X.; Zhang, T.; Li, Y.; Yan, P. DRD3 Ser9Gly polymorphism and treatment response to antipsychotics in schizophrenia: A meta-analysis. Neurosci. Lett. 2022, 786, 136788. [Google Scholar] [CrossRef]
  77. Hattori, E.; Nakajima, M.; Yamada, K.; Iwayama, Y.; Toyota, T.; Saitou, N.; Yoshikawa, T. Variable number of tandem repeat polymorphisms of DRD4: Re-evaluation of selection hypothesis and analysis of association with schizophrenia. Eur. J. Hum. Genet. 2009, 17, 793–801. [Google Scholar] [CrossRef]
  78. Michaelides, M.; Pascau, J.; Gispert, J.D.; Delis, F.; Grandy, D.K.; Wang, G.J.; Desco, M.; Rubinstein, M.; Volkow, N.D.; Thanos, P.K. Dopamine D4 receptors modulate brain metabolic activity in the prefrontal cortex and cerebellum at rest and in response to methylphenidate. Eur. J. Neurosci. 2010, 32, 668–676. [Google Scholar] [CrossRef] [PubMed]
  79. Daly, G.; Hawi, Z.; Fitzgerald, M.; Gill, M. Mapping susceptibility loci in attention deficit hyperactivity disorder: Preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol. Psychiatry 1999, 4, 192–196. [Google Scholar] [CrossRef] [PubMed]
  80. Huhtala, T.; Poutiainen, P.; Rytkönen, J.; Lehtimäki, K.; Parkkari, T.; Kasanen, I.; Airaksinen, A.J.; Koivula, T.; Sweeney, P.; Kontkanen, O.; et al. Improved synthesis of [18F] fallypride and characterization of a Huntington’s disease mouse model, zQ175DN KI, using longitudinal PET imaging of D2/D3 receptors. EJNMMI Radiopharm. Chem. 2019, 4, 20. [Google Scholar] [CrossRef] [PubMed]
  81. Mukherjee, J.; Christian, B.T.; Dunigan, K.A.; Shi, B.; Narayanan, T.K.; Satter, M.; Mantil, J. Brain imaging of 18F-fallypride in normal volunteers: Blood analysis, distribution, test-retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D-2/D-3 receptors. Synapse 2002, 46, 170–188. [Google Scholar] [CrossRef]
  82. Svensson, J.E.; Schain, M.; Plavén-Sigray, P.; Cervenka, S.; Tiger, M.; Nord, M.; Halldin, C.; Farde, L.; Lundberg, J. Validity and reliability of extrastriatal [11C]raclopride binding quantification in the living human brain. Neuroimage 2019, 202, 116143. [Google Scholar] [CrossRef] [PubMed]
  83. Tziortzi, A.C.; Searle, G.E.; Tzimopoulou, S.; Salinas, C.; Beaver, J.D.; Jenkinson, M.; Laruelle, M.; Rabiner, E.A.; Gunn, R.N. Imaging dopamine receptors in humans with [11C]-(+)-PHNO: Dissection of D3 signal and anatomy. Neuroimage 2011, 54, 264–277. [Google Scholar] [CrossRef]
  84. Centonze, D.; Grande, C.; Saulle, E.; Martin, A.B.; Gubellini, P.; Pavon, N.; Pisani, A.; Bernardi, G.; Moratalla, R.; Calabresi, P. Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity. J. Neurosci. 2003, 23, 8506–8512. [Google Scholar] [CrossRef]
  85. Tepper, J.M.; Abercrombie, E.D.; Bolam, J.P. Basal ganglia macrocircuits. Prog. Brain Res. 2007, 160, 3–7. [Google Scholar] [CrossRef] [PubMed]
  86. Leisman, G.; Braun-Benjamin, O.; Melillo, R. Cognitive-motor interactions of the basal ganglia in development. Front. Syst. Neurosci. 2014, 8, 16. [Google Scholar] [CrossRef]
  87. Schmitt, L. Caudate Nucleus. In Encyclopedia of Autism Spectrum Disorders; Volkmar, F.R., Ed.; Springer: New York, NY, USA, 2013; pp. 538–544. [Google Scholar]
  88. Frank, M.J.; Loughry, B.; O’Reilly, R.C. Interactions between frontal cortex and basal ganglia in working memory: A computational model. Cogn. Affect. Behav. Neurosci. 2001, 1, 137–160. [Google Scholar] [CrossRef] [PubMed]
  89. Graybiel, A.M.; Aosaki, T.; Flaherty, A.W.; Kimura, M. The basal ganglia and adaptive motor control. Science 1994, 265, 1826–1831. [Google Scholar] [CrossRef]
  90. Cazorla, M.; de Carvalho, F.D.; Chohan, M.O.; Shegda, M.; Chuhma, N.; Rayport, S.; Ahmari, S.E.; Moore, H.; Kellendonk, C. Dopamine D2 receptors regulate the anatomical and functional balance of basal ganglia circuitry. Neuron 2014, 81, 153–164. [Google Scholar] [CrossRef]
  91. Guttman, M.; Seeman, P. L-dopa reverses the elevated density of D2 dopamine receptors in Parkinson’s diseased striatum. J. Neural Transm. 1985, 64, 93–103. [Google Scholar] [CrossRef]
  92. Stoof, J.C.; De Boer, T.; Sminia, P.; Mulder, A.H. Stimulation of D2-dopamine receptors in rat neostriatum inhibits the release of acetylcholine and dopamine but does not affect the release of γ-aminobutyric acid, glutamate or serotonin. Eur. J. Pharmacol. 1982, 84, 211–214. [Google Scholar] [CrossRef]
  93. Seeman, P.; Bzowej, N.H.; Guan, H.C.; Bergeron, C.; Reynolds, G.P.; Bird, E.D.; Riederer, P.; Jellinger, K.; Tourtellotte, W.W. Human brain D1 and D2 dopamine receptors in schizophrenia, Alzheimer’s, Parkinson’s, and Huntington’s diseases. Neuropsychopharmacology 1987, 1, 5–15. [Google Scholar] [CrossRef] [PubMed]
  94. Wang, J.; Cheng, Y.; Wang, X.; Roltsch Hellard, E.; Ma, T.; Gil, H.; Ben Hamida, S.; Ron, D. Alcohol Elicits Functional and Structural Plasticity Selectively in Dopamine D1 Receptor-Expressing Neurons of the Dorsomedial Striatum. J. Neurosci. 2015, 35, 11634–11643. [Google Scholar] [CrossRef] [PubMed]
  95. Bergonzoni, G.; Döring, J.; Biagioli, M. D1R- and D2R-Medium-Sized Spiny Neurons Diversity: Insights into Striatal Vulnerability to Huntington’s Disease Mutation. Front. Cell. Neurosci. 2021, 15, 628010. [Google Scholar] [CrossRef]
  96. Perreault, M.; Hasbi, A.; O’Dowd, B.; George, S. The Dopamine D1–D2 Receptor Heteromer in Striatal Medium Spiny Neurons: Evidence for a Third Distinct Neuronal Pathway in Basal Ganglia. Front. Neuroanat. 2011, 5, 31. [Google Scholar] [CrossRef] [PubMed]
  97. Goutier, W.; Lowry, J.P.; McCreary, A.C.; O’Connor, J.J. Frequency-Dependent Modulation of Dopamine Release by Nicotine and Dopamine D1 Receptor Ligands: An In Vitro Fast Cyclic Voltammetry Study in Rat Striatum. Neurochem. Res. 2016, 41, 945–950. [Google Scholar] [CrossRef] [PubMed]
  98. Spina, L.; Fenu, S.; Longoni, R.; Rivas, E.; Di Chiara, G. Nicotine-conditioned single-trial place preference: Selective role of nucleus accumbens shell dopamine D1 receptors in acquisition. Psychopharmacology 2006, 184, 447–455. [Google Scholar] [CrossRef] [PubMed]
  99. Centonze, D.; Grande, C.; Usiello, A.; Gubellini, P.; Erbs, E.; Martin, A.B.; Pisani, A.; Tognazzi, N.; Bernardi, G.; Moratalla, R.; et al. Receptor subtypes involved in the presynaptic and postsynaptic actions of dopamine on striatal interneurons. J. Neurosci. 2003, 23, 6245–6254. [Google Scholar] [CrossRef] [PubMed]
  100. Stahl, S.M. Dazzled by the dominions of dopamine: Clinical roles of D3, D2, and D1 receptors. CNS Spectr. 2017, 22, 305–311. [Google Scholar] [CrossRef] [PubMed]
  101. Mishra, A.; Singh, S.; Shukla, S. Physiological and Functional Basis of Dopamine Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson’s disease. J. Exp. Neurosci. 2018, 12, 1179069518779829. [Google Scholar] [CrossRef]
  102. Dubois, A.; Savasta, M.; Curet, O.; Scatton, B. Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors. Neuroscience 1986, 19, 125–137. [Google Scholar] [CrossRef]
  103. Sumiyoshi, T.; Kunugi, H.; Nakagome, K. Serotonin and dopamine receptors in motivational and cognitive disturbances of schizophrenia. Front. Neurosci. 2014, 8, 395. [Google Scholar] [CrossRef] [PubMed]
  104. Surmeier, D.J.; Song, W.J.; Yan, Z. Coordinated expression of dopamine receptors in neostriatal medium spiny neurons. J. Neurosci. 1996, 16, 6579–6591. [Google Scholar] [CrossRef] [PubMed]
  105. Seeman, P.; Nam, D.; Ulpian, C.; Liu, I.S.; Tallerico, T. New dopamine receptor, D2Longer, with unique TG splice site, in human brain. Brain Res. Mol. Brain Res. 2000, 76, 132–141. [Google Scholar] [CrossRef] [PubMed]
  106. Richfield, E.K.; Young, A.B.; Penney, J.B. Properties of D2 dopamine receptor autoradiography: High percentage of high-affinity agonist sites and increased nucleotide sensitivity in tissue sections. Brain Res. 1986, 383, 121–128. [Google Scholar] [CrossRef]
  107. Suzuki, M.; Hurd, Y.L.; Sokoloff, P.; Schwartz, J.C.; Sedvall, G. D3 dopamine receptor mRNA is widely expressed in the human brain. Brain Res. 1998, 779, 58–74. [Google Scholar] [CrossRef] [PubMed]
  108. Corbit, L.H.; Nie, H.; Janak, P.H. Habitual responding for alcohol depends upon both AMPA and D2 receptor signaling in the dorsolateral striatum. Front. Behav. Neurosci. 2014, 8, 301. [Google Scholar] [CrossRef]
  109. Alcantara, A.A.; Chen, V.; Herring, B.E.; Mendenhall, J.M.; Berlanga, M.L. Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and nucleus accumbens of the rat. Brain Res. 2003, 986, 22–29. [Google Scholar] [CrossRef] [PubMed]
  110. Maurice, N.; Mercer, J.; Chan, C.S.; Hernandez-Lopez, S.; Held, J.; Tkatch, T.; Surmeier, D.J. D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons. J. Neurosci. 2004, 24, 10289–10301. [Google Scholar] [CrossRef]
  111. Gallo, E.F.; Greenwald, J.; Yeisley, J.; Teboul, E.; Martyniuk, K.M.; Villarin, J.M.; Li, Y.; Javitch, J.A.; Balsam, P.D.; Kellendonk, C. Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning. Mol. Psychiatry 2022, 27, 1502–1514. [Google Scholar] [CrossRef]
  112. Cavallaro, J.; Yeisley, J.; Akdoǧan, B.; Salazar, R.E.; Floeder, J.R.; Balsam, P.D.; Gallo, E.F. Dopamine D2 receptors in nucleus accumbens cholinergic interneurons increase impulsive choice. Neuropsychopharmacology 2023, 48, 1309–1317. [Google Scholar] [CrossRef]
  113. Johnson, A.E.; Coirini, H.; Kallstrom, L.; Wiesel, F.A. Characterization of dopamine receptor binding sites in the subthalamic nucleus. Neuroreport 1994, 5, 1836–1838. [Google Scholar] [CrossRef]
  114. Roman, K.M.; Briscione, M.A.; Donsante, Y.; Ingram, J.; Fan, X.; Bernhard, D.; Campbell, S.A.; Downs, A.M.; Gutman, D.; Sardar, T.A.; et al. Striatal Subregion-selective Dysregulated Dopamine Receptor-mediated Intracellular Signaling in a Model of DOPA-responsive Dystonia. Neuroscience 2023, 517, 37–49. [Google Scholar] [CrossRef]
  115. Likhite, N.; Jackson, C.A.; Liang, M.S.; Krzyzanowski, M.C.; Lei, P.; Wood, J.F.; Birkaya, B.; Michaels, K.L.; Andreadis, S.T.; Clark, S.D.; et al. The protein arginine methyltransferase PRMT5 promotes D2-like dopamine receptor signaling. Sci. Signal. 2015, 8, ra115. [Google Scholar] [CrossRef]
  116. Esmaeili, M.H.; Kermani, M.; Parvishan, A.; Haghparast, A. Role of D1/D2 dopamine receptors in the CA1 region of the rat hippocampus in the rewarding effects of morphine administered into the ventral tegmental area. Behav. Brain Res. 2012, 231, 111–115. [Google Scholar] [CrossRef]
  117. Fremeau, R.T., Jr.; Duncan, G.E.; Fornaretto, M.G.; Dearry, A.; Gingrich, J.A.; Breese, G.R.; Caron, M.G. Localization of D1 dopamine receptor mRNA in brain supports a role in cognitive, affective, and neuroendocrine aspects of dopaminergic neurotransmission. Proc. Natl. Acad. Sci. USA 1991, 88, 3772–3776. [Google Scholar] [CrossRef]
  118. Groenewegen, H.J.; Wright, C.I.; Beijer, A.V.; Voorn, P. Convergence and segregation of ventral striatal inputs and outputs. Ann. N. Y. Acad. Sci. 1999, 877, 49–63. [Google Scholar] [CrossRef]
  119. Scofield, M.D.; Heinsbroek, J.A.; Gipson, C.D.; Kupchik, Y.M.; Spencer, S.; Smith, A.C.; Roberts-Wolfe, D.; Kalivas, P.W. The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis. Pharmacol. Rev. 2016, 68, 816–871. [Google Scholar] [CrossRef]
  120. Bhimani, R.V.; Yates, R.; Bass, C.E.; Park, J. Distinct limbic dopamine regulation across olfactory-tubercle subregions through integration of in vivo fast-scan cyclic voltammetry and optogenetics. J. Neurochem. 2022, 161, 53–68. [Google Scholar] [CrossRef]
  121. Muly, E.C.; Maddox, M.; Khan, Z.U. Distribution of D1 and D5 dopamine receptors in the primate nucleus accumbens. Neuroscience 2010, 169, 1557–1566. [Google Scholar] [CrossRef]
  122. De Keyser, J.; Claeys, A.; De Backer, J.P.; Ebinger, G.; Roels, F.; Vauquelin, G. Autoradiographic localization of D1 and D2 dopamine receptors in the human brain. Neurosci. Lett. 1988, 91, 142–147. [Google Scholar] [CrossRef]
  123. Nishi, A.; Kuroiwa, M.; Shuto, T. Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front. Neuroanat. 2011, 5, 43. [Google Scholar] [CrossRef]
  124. Wise, R.A.; Jordan, C.J. Dopamine, behavior, and addiction. J. Biomed. Sci. 2021, 28, 83. [Google Scholar] [CrossRef]
  125. Stahl, S.M. Drugs for psychosis and mood: Unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectr. 2017, 22, 375–384. [Google Scholar] [CrossRef]
  126. Hasbi, A.; Perreault, M.L.; Shen, M.Y.F.; Fan, T.; Nguyen, T.; Alijaniaram, M.; Banasikowski, T.J.; Grace, A.A.; O’Dowd, B.F.; Fletcher, P.J.; et al. Activation of Dopamine D1-D2 Receptor Complex Attenuates Cocaine Reward and Reinstatement of Cocaine-Seeking through Inhibition of DARPP-32, ERK, and DeltaFosB. Front. Pharmacol. 2017, 8, 924. [Google Scholar] [CrossRef]
  127. Jia, W.; Kawahata, I.; Cheng, A.; Sasaki, T.; Sasaoka, T.; Fukunaga, K. Amelioration of Nicotine-Induced Conditioned Place Preference Behaviors in Mice by an FABP3 Inhibitor. Int. J. Mol. Sci. 2023, 24, 6644. [Google Scholar] [CrossRef]
  128. Jia, W.; Kawahata, I.; Cheng, A.; Fukunaga, K. The Role of CaMKII and ERK Signaling in Addiction. Int. J. Mol. Sci. 2021, 22, 3189. [Google Scholar] [CrossRef]
  129. Jia, W.; Wilar, G.; Kawahata, I.; Cheng, A.; Fukunaga, K. Impaired Acquisition of Nicotine-Induced Conditioned Place Preference in Fatty Acid-Binding Protein 3 Null Mice. Mol. Neurobiol. 2021, 58, 2030–2045. [Google Scholar] [CrossRef]
  130. Bono, F.; Mutti, V.; Fiorentini, C.; Missale, C. Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection. Biomolecules 2020, 10, 1016. [Google Scholar] [CrossRef]
  131. Bono, F.; Mutti, V.; Tomasoni, Z.; Sbrini, G.; Missale, C.; Fiorentini, C. Recent Advances in Dopamine D3 Receptor Heterodimers: Focus on Dopamine D3 and D1 Receptor–Receptor Interaction and Striatal Function. In Therapeutic Applications of Dopamine D3 Receptor Function: New Insight after 30 Years of Research; Boileau, I., Collo, G., Eds.; Springer International Publishing: Cham, Switzerland, 2023; pp. 47–72. [Google Scholar]
  132. Welch, A.C.; Zhang, J.; Lyu, J.; McMurray, M.S.; Javitch, J.A.; Kellendonk, C.; Dulawa, S.C. Dopamine D2 receptor overexpression in the nucleus accumbens core induces robust weight loss during scheduled fasting selectively in female mice. Mol. Psychiatry 2021, 26, 3765–3777. [Google Scholar] [CrossRef]
  133. Perreault, M.L.; Hasbi, A.; O’Dowd, B.F.; George, S.R. Heteromeric dopamine receptor signaling complexes: Emerging neurobiology and disease relevance. Neuropsychopharmacology 2014, 39, 156–168. [Google Scholar] [CrossRef] [PubMed]
  134. Maggio, R.; Aloisi, G.; Silvano, E.; Rossi, M.; Millan, M.J. Heterodimerization of dopamine receptors: New insights into functional and therapeutic significance. Parkinsonism Relat. Disord. 2009, 15 (Suppl. S4), S2–S7. [Google Scholar] [CrossRef]
  135. Vekshina, N.L.; Anokhin, P.K.; Veretinskaya, A.G.; Shamakina, I.Y. Dopamine D1–D2 receptor heterodimers: A literature review. Biochem. (Mosc.) Suppl. Ser. B Biomed. Chem. 2017, 11, 111–119. [Google Scholar] [CrossRef]
  136. Tritsch, N.X.; Sabatini, B.L. Dopaminergic Modulation of Synaptic Transmission in Cortex and Striatum. Neuron 2012, 76, 33–50. [Google Scholar] [CrossRef]
  137. Paspalas, C.D.; Rakic, P.; Goldman-Rakic, P.S. Internalization of D2 dopamine receptors is clathrin-dependent and select to dendro-axonic appositions in primate prefrontal cortex. Eur. J. Neurosci. 2006, 24, 1395–1403. [Google Scholar] [CrossRef]
  138. Mladinov, M.; Mayer, D.; Brčić, L.; Wolstencroft, E.; Man, N.; Holt, I.; Hof, P.; Morris, G.; Šimić, G. Astrocyte expression of D2-like dopamine receptors in the prefrontal cortex. Transl. Neurosci. 2010, 1, 238–243. [Google Scholar] [CrossRef]
  139. Wulaer, B.; Kunisawa, K.; Tanabe, M.; Yanagawa, A.; Saito, K.; Mouri, A.; Nabeshima, T. Pharmacological blockade of dopamine D1- or D2-receptor in the prefrontal cortex induces attentional impairment in the object-based attention test through different neuronal circuits in mice. Mol. Brain 2021, 14, 43. [Google Scholar] [CrossRef]
  140. Mahmoodkhani, M.; Ghasemi, M.; Derafshpour, L.; Amini, M.; Mehranfard, N. Developmental effects of early-life stress on dopamine D2 receptor and proteins involved in noncanonical D2 dopamine receptor signaling pathway in the prefrontal cortex of male rats. J. Complement. Integr. Med. 2021, 19, 697–703. [Google Scholar] [CrossRef]
  141. Subburaju, S.; Sromek, A.W.; Seeman, P.; Neumeyer, J.L. The High Affinity Dopamine D2 Receptor Agonist MCL-536: A New Tool for Studying Dopaminergic Contribution to Neurological Disorders. ACS Chem. Neurosci. 2021, 12, 1428–1437. [Google Scholar] [CrossRef]
  142. Alam, S.I.; Jo, M.G.; Park, T.J.; Ullah, R.; Ahmad, S.; Rehman, S.U.; Kim, M.O. Quinpirole-Mediated Regulation of Dopamine D2 Receptors Inhibits Glial Cell-Induced Neuroinflammation in Cortex and Striatum after Brain Injury. Biomedicines 2021, 9, 47. [Google Scholar] [CrossRef]
  143. Cai, G.; Wang, H.Y.; Friedman, E. Increased dopamine receptor signaling and dopamine receptor-G protein coupling in denervated striatum. J. Pharmacol. Exp. Ther. 2002, 302, 1105–1112. [Google Scholar] [CrossRef] [PubMed]
  144. Marcott, P.F.; Gong, S.; Donthamsetti, P.; Grinnell, S.G.; Nelson, M.N.; Newman, A.H.; Birnbaumer, L.; Martemyanov, K.A.; Javitch, J.A.; Ford, C.P. Regional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens. Neuron 2018, 98, 575–587.e4. [Google Scholar] [CrossRef]
  145. Gong, S.; Fayette, N.; Heinsbroek, J.A.; Ford, C.P. Cocaine shifts dopamine D2 receptor sensitivity to gate conditioned behaviors. Neuron 2021, 109, 3421–3435.e25. [Google Scholar] [CrossRef]
  146. Lewis, R.G.; Serra, M.; Radl, D.; Gori, M.; Tran, C.; Michalak, S.E.; Vanderwal, C.D.; Borrelli, E. Dopaminergic Control of Striatal Cholinergic Interneurons Underlies Cocaine-Induced Psychostimulation. Cell Rep. 2020, 31, 107527. [Google Scholar] [CrossRef]
  147. Del’guidice, T.; Lemasson, M.; Beaulieu, J.M. Role of Beta-arrestin 2 downstream of dopamine receptors in the Basal Ganglia. Front. Neuroanat. 2011, 5, 58. [Google Scholar] [CrossRef]
  148. Urs, N.M.; Gee, S.M.; Pack, T.F.; McCorvy, J.D.; Evron, T.; Snyder, J.C.; Yang, X.; Rodriguiz, R.M.; Borrelli, E.; Wetsel, W.C.; et al. Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties. Proc. Natl. Acad. Sci. USA 2016, 113, E8178–E8186. [Google Scholar] [CrossRef]
  149. Urs, N.M.; Peterson, S.M.; Caron, M.G. New Concepts in Dopamine D2 Receptor Biased Signaling and Implications for Schizophrenia Therapy. Biol. Psychiatry 2017, 81, 78–85. [Google Scholar] [CrossRef]
  150. Matsumoto, M.; Hidaka, K.; Akiho, H.; Tada, S.; Okada, M.; Yamaguchi, T. Low stringency hybridization study of the dopamine D4 receptor revealed D4-like mRNA distribution of the orphan seven-transmembrane receptor, APJ, in human brain. Neurosci. Lett. 1996, 219, 119–122. [Google Scholar] [CrossRef]
  151. Yuen, E.Y.; Yan, Z. Dopamine D4 receptors regulate AMPA receptor trafficking and glutamatergic transmission in GABAergic interneurons of prefrontal cortex. J. Neurosci. 2009, 29, 550–562. [Google Scholar] [CrossRef]
  152. Graziane, N.M.; Yuen, E.Y.; Yan, Z. Dopamine D4 Receptors Regulate GABAA Receptor Trafficking via an Actin/Cofilin/Myosin-dependent Mechanism. J. Biol. Chem. 2009, 284, 8329–8336. [Google Scholar] [CrossRef]
  153. Magill, P.J.; Bolam, J.P.; Bevan, M.D. Dopamine regulates the impact of the cerebral cortex on the subthalamic nucleus–globus pallidus network. Neuroscience 2001, 106, 313–330. [Google Scholar] [CrossRef]
  154. Emmi, A.; Campagnolo, M.; Stocco, E.; Carecchio, M.; Macchi, V.; Antonini, A.; De Caro, R.; Porzionato, A. Neurotransmitter and receptor systems in the subthalamic nucleus. Brain Struct. Funct. 2023, 228, 1595–1617. [Google Scholar] [CrossRef]
  155. Kaur, S.; Singh, S.; Jaiswal, G.; Kumar, S.; Hourani, W.; Gorain, B.; Kumar, P. Pharmacology of Dopamine and Its Receptors. In Frontiers in Pharmacology of Neurotransmitters; Kumar, P., Deb, P.K., Eds.; Springer: Singapore, 2020; pp. 143–182. [Google Scholar]
  156. Galvan, A.; Hu, X.; Rommelfanger, K.S.; Pare, J.F.; Khan, Z.U.; Smith, Y.; Wichmann, T. Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys. J. Neurophysiol. 2014, 112, 467–479. [Google Scholar] [CrossRef]
  157. Hurd, Y.L.; Suzuki, M.; Sedvall, G.C. D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. J. Chem. Neuroanat. 2001, 22, 127–137. [Google Scholar] [CrossRef]
  158. Dawson, T.M.; Gehlert, D.R.; McCabe, R.T.; Barnett, A.; Wamsley, J.K. D-1 dopamine receptors in the rat brain: A quantitative autoradiographic analysis. J. Neurosci. 1986, 6, 2352–2365. [Google Scholar] [CrossRef]
  159. Wang, X.S.; Ong, W.Y.; Lee, H.K.; Huganir, R.L. A light and electron microscopic study of glutamate receptors in the monkey subthalamic nucleus. J. Neurocytol. 2000, 29, 743–754. [Google Scholar] [CrossRef]
  160. Emmi, A.; Antonini, A.; Sandre, M.; Baldo, A.; Contran, M.; Macchi, V.; Guidolin, D.; Porzionato, A.; De Caro, R. Topography and distribution of adenosine A2A and dopamine D2 receptors in the human Subthalamic Nucleus. Front. Neurosci. 2022, 16, 945574. [Google Scholar] [CrossRef]
  161. Gross, G.; Drescher, K. The role of dopamine D3 receptors in antipsychotic activity and cognitive functions. Handb. Exp. Pharmacol. 2012, 167–210. [Google Scholar]
  162. Nakajima, S.; Gerretsen, P.; Takeuchi, H.; Caravaggio, F.; Chow, T.; Le Foll, B.; Mulsant, B.; Pollock, B.; Graff-Guerrero, A. The potential role of dopamine D3 receptor neurotransmission in cognition. Eur. Neuropsychopharmacol. 2013, 23, 799–813. [Google Scholar] [CrossRef]
  163. Mehta, T.R.; Murala, S.; Siddiqui, J. Dopamine. In Neurochemistry in Clinical Practice; Bollu, P.C., Ed.; Springer International Publishing: Cham, Switzerland, 2022; pp. 1–23. [Google Scholar]
  164. Muly, E.C.; Senyuz, M.; Khan, Z.U.; Guo, J.D.; Hazra, R.; Rainnie, D.G. Distribution of D1 and D5 dopamine receptors in the primate and rat basolateral amygdala. Brain Struct. Funct. 2009, 213, 375–393. [Google Scholar] [CrossRef]
  165. Lintas, A.; Chi, N.; Lauzon, N.M.; Bishop, S.F.; Gholizadeh, S.; Sun, N.; Tan, H.; Laviolette, S.R. Identification of a dopamine receptor-mediated opiate reward memory switch in the basolateral amygdala-nucleus accumbens circuit. J. Neurosci. 2011, 31, 11172–11183. [Google Scholar] [CrossRef]
  166. Takahashi, H.; Takano, H.; Kodaka, F.; Arakawa, R.; Yamada, M.; Otsuka, T.; Hirano, Y.; Kikyo, H.; Okubo, Y.; Kato, M.; et al. Contribution of dopamine D1 and D2 receptors to amygdala activity in human. J. Neurosci. 2010, 30, 3043–3047. [Google Scholar] [CrossRef]
  167. Wu, J.; Xiao, H.; Sun, H.; Zou, L.; Zhu, L.-Q. Role of Dopamine Receptors in ADHD: A Systematic Meta-analysis. Mol. Neurobiol. 2012, 45, 605–620. [Google Scholar] [CrossRef] [PubMed]
  168. de la Mora, M.P.; Gallegos-Cari, A.; Arizmendi-García, Y.; Marcellino, D.; Fuxe, K. Role of dopamine receptor mechanisms in the amygdaloid modulation of fear and anxiety: Structural and functional analysis. Prog. Neurobiol. 2010, 90, 198–216. [Google Scholar] [CrossRef]
  169. Ferré, S.; Belcher, A.M.; Bonaventura, J.; Quiroz, C.; Sánchez-Soto, M.; Casadó-Anguera, V.; Cai, N.S.; Moreno, E.; Boateng, C.A.; Keck, T.M.; et al. Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants. Front. Endocrinol. 2022, 13, 1014678. [Google Scholar] [CrossRef]
  170. Kempadoo, K.A.; Mosharov, E.V.; Choi, S.J.; Sulzer, D.; Kandel, E.R. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc. Natl. Acad. Sci. USA 2016, 113, 14835–14840. [Google Scholar] [CrossRef]
  171. Tsetsenis, T.; Broussard, J.I.; Dani, J.A. Dopaminergic regulation of hippocampal plasticity, learning, and memory. Front. Behav. Neurosci. 2023, 16, 1092420. [Google Scholar] [CrossRef]
  172. Edelmann, E.; Lessmann, V. Dopaminergic innervation and modulation of hippocampal networks. Cell Tissue Res. 2018, 373, 711–727. [Google Scholar] [CrossRef]
  173. Pan, X.; Kaminga, A.C.; Wen, S.W.; Wu, X.; Acheampong, K.; Liu, A. Dopamine and Dopamine Receptors in Alzheimer’s Disease: A Systematic Review and Network Meta-Analysis. Front. Aging Neurosci. 2019, 11, 175. [Google Scholar] [CrossRef] [PubMed]
  174. Martorana, A.; Koch, G. Is dopamine involved in Alzheimer’s disease? Front. Aging Neurosci. 2014, 6, 252. [Google Scholar] [CrossRef]
  175. Sala, A.; Caminiti, S.P.; Presotto, L.; Pilotto, A.; Liguori, C.; Chiaravalloti, A.; Garibotto, V.; Frisoni, G.B.; D’Amelio, M.; Paghera, B.; et al. In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer’s disease phases. Alzheimers Res. Ther. 2021, 13, 187. [Google Scholar] [CrossRef]
  176. Zhang, X.-L.; Liu, S.; Sun, Q.; Zhu, J.-X. Dopamine Receptors in the Gastrointestinal Tract. In Dopamine in the Gut; Zhu, J.-X., Ed.; Springer: Singapore, 2021; pp. 53–85. [Google Scholar]
  177. Prieto, G.A. Abnormalities of Dopamine D3 Receptor Signaling in the Diseased Brain. J. Cent. Nerv. Syst. Dis. 2017, 9, 1179573517726335. [Google Scholar] [CrossRef]
  178. Latif, S.; Jahangeer, M.; Maknoon Razia, D.; Ashiq, M.; Ghaffar, A.; Akram, M.; El Allam, A.; Bouyahya, A.; Garipova, L.; Ali Shariati, M.; et al. Dopamine in Parkinson’s disease. Clin. Chim. Acta 2021, 522, 114–126. [Google Scholar] [CrossRef] [PubMed]
  179. Prasad, E.M.; Hung, S.Y. Current Therapies in Clinical Trials of Parkinson’s Disease: A 2021 Update. Pharmaceuticals 2021, 14, 717. [Google Scholar] [CrossRef]
  180. Robertson, H.A. Synergistic interactions of D1- and D2-selective dopamine agonists in animal models for Parkinson’s disease: Sites of action and implications for the pathogenesis of dyskinesias. Can. J. Neurol. Sci. 1992, 19, 147–152. [Google Scholar] [CrossRef]
  181. Shetty, A.S.; Bhatia, K.P.; Lang, A.E. Dystonia and Parkinson’s disease: What is the relationship? Neurobiol. Dis. 2019, 132, 104462. [Google Scholar] [CrossRef]
  182. Kawahata, I.; Fukunaga, K. Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia. Int. J. Mol. Sci. 2020, 21, 3779. [Google Scholar] [CrossRef]
  183. Kawahata, I.; Fukunaga, K. Impact of fatty acid-binding proteins and dopamine receptors on α-synucleinopathy. J. Pharmacol. Sci. 2022, 148, 248–254. [Google Scholar] [CrossRef]
  184. Mansvelder, H.D.; McGehee, D.S. Cellular and synaptic mechanisms of nicotine addiction. J. Neurobiol. 2002, 53, 606–617. [Google Scholar] [CrossRef]
  185. Kauer, J.A. Learning mechanisms in addiction: Synaptic plasticity in the ventral tegmental area as a result of exposure to drugs of abuse. Annu. Rev. Physiol. 2004, 66, 447–475. [Google Scholar] [CrossRef] [PubMed]
  186. Picciotto, M.R.; Corrigall, W.A. Neuronal systems underlying behaviors related to nicotine addiction: Neural circuits and molecular genetics. J. Neurosci. 2002, 22, 3338–3341. [Google Scholar] [CrossRef] [PubMed]
  187. Clarke, R.; Adermark, L. Dopaminergic Regulation of Striatal Interneurons in Reward and Addiction: Focus on Alcohol. Neural Plast. 2015, 2015, 814567. [Google Scholar] [CrossRef] [PubMed]
  188. Kawahata, I.; Ohtaku, S.; Tomioka, Y.; Ichinose, H.; Yamakuni, T. Dopamine or biopterin deficiency potentiates phosphorylation at 40Ser and ubiquitination of tyrosine hydroxylase to be degraded by the ubiquitin proteasome system. Biochem. Biophys. Res. Commun. 2015, 465, 53–58. [Google Scholar] [CrossRef]
  189. Radnikow, G.; Misgeld, U. Dopamine D1 receptors facilitate GABAA synaptic currents in the rat substantia nigra pars reticulata. J. Neurosci. 1998, 18, 2009–2016. [Google Scholar] [CrossRef] [PubMed]
  190. Villar-Cheda, B.; Rodríguez-Pallares, J.; Valenzuela, R.; Muñoz, A.; Guerra, M.J.; Baltatu, O.C.; Labandeira-Garcia, J.L. Nigral and striatal regulation of angiotensin receptor expression by dopamine and angiotensin in rodents: Implications for progression of Parkinson’s disease. Eur. J. Neurosci. 2010, 32, 1695–1706. [Google Scholar] [CrossRef] [PubMed]
  191. Kliem, M.A.; Maidment, N.T.; Ackerson, L.C.; Chen, S.; Smith, Y.; Wichmann, T. Activation of nigral and pallidal dopamine D1-like receptors modulates basal ganglia outflow in monkeys. J. Neurophysiol. 2007, 98, 1489–1500. [Google Scholar] [CrossRef]
  192. Lahiri, A.K.; Bevan, M.D. Dopaminergic Transmission Rapidly and Persistently Enhances Excitability of D1 Receptor-Expressing Striatal Projection Neurons. Neuron 2020, 106, 277–290.e6. [Google Scholar] [CrossRef] [PubMed]
  193. Huang, Q.; Zhou, D.; Chase, K.; Gusella, J.F.; Aronin, N.; DiFiglia, M. Immunohistochemical localization of the D1 dopamine receptor in rat brain reveals its axonal transport, pre- and postsynaptic localization, and prevalence in the basal ganglia, limbic system, and thalamic reticular nucleus. Proc. Natl. Acad. Sci. USA 1992, 89, 11988–11992. [Google Scholar] [CrossRef] [PubMed]
  194. Zhuang, Y.; Xu, P.; Mao, C.; Wang, L.; Krumm, B.; Zhou, X.E.; Huang, S.; Liu, H.; Cheng, X.; Huang, X.P.; et al. Structural insights into the human D1 and D2 dopamine receptor signaling complexes. Cell 2021, 184, 931–942. [Google Scholar] [CrossRef] [PubMed]
  195. Rani, M.; Kanungo, M.S. Expression of D2 dopamine receptor in the mouse brain. Biochem. Biophys. Res. Commun. 2006, 344, 981–986. [Google Scholar] [CrossRef]
  196. Nagatsu, T.; Levitt, M.; Udenfriend, S. Tyrosine Hydroxylase. The initial step in norepinephrine biosynthesis. J. Biol. Chem. 1964, 239, 2910–2917. [Google Scholar] [CrossRef]
  197. Nagatsu, T. Change of tyrosine hydroxylase in the parkinsonian brain and in the brain of MPTP-treated mice as revealed by homospecific activity. Neurochem. Res. 1990, 15, 425–429. [Google Scholar] [CrossRef]
  198. Nagatsu, T. The catecholamine system in health and disease—Relation to tyrosine 3-monooxygenase and other catecholamine-synthesizing enzymes. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2007, 82, 388–415. [Google Scholar] [CrossRef]
  199. Nagatsu, T.; Nagatsu, I. Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson’s disease (PD): Historical overview and future prospects. J. Neural Transm. 2016, 123, 1255–1278. [Google Scholar] [CrossRef]
  200. Nagatsu, T. Catecholamines and Parkinson’s disease: Tyrosine hydroxylase (TH) over tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH1) to cytokines, neuromelanin, and gene therapy: A historical overview. J. Neural Transm. 2023, 1–14. [Google Scholar] [CrossRef]
  201. Salvatore, M.F.; Kasanga, E.A.; Kelley, D.P.; Venable, K.E.; McInnis, T.R.; Cantu, M.A.; Terrebonne, J.; Lanza, K.; Meadows, S.M.; Centner, A.; et al. Modulation of nigral dopamine signaling mitigates parkinsonian signs of aging: Evidence from intervention with calorie restriction or inhibition of dopamine uptake. Geroscience 2023, 45, 45–63. [Google Scholar] [CrossRef]
  202. Salvatore, M.F.; Terrebonne, J.; Cantu, M.A.; McInnis, T.R.; Venable, K.; Kelley, P.; Kasanga, E.A.; Latimer, B.; Owens, C.L.; Pruett, B.S.; et al. Dissociation of Striatal Dopamine and Tyrosine Hydroxylase Expression from Aging-Related Motor Decline: Evidence from Calorie Restriction Intervention. J. Gerontol. A Biol. Sci. Med. Sci. 2017, 73, 11–20. [Google Scholar] [CrossRef] [PubMed]
  203. Trevitt, J.; Carlson, B.; Nowend, K.; Salamone, J. Substantia nigra pars reticulata is a highly potent site of action for the behavioral effects of the D1 antagonist SCH 23390 in the rat. Psychopharmacology 2001, 156, 32–41. [Google Scholar] [CrossRef]
  204. Li, H.; Feng, Y.; Chen, Z.; Jiang, X.; Zhou, Z.; Yuan, J.; Li, F.; Zhang, Y.; Huang, X.; Fan, S.; et al. Pepper component 7-ethoxy-4-methylcoumarin, a novel dopamine D2 receptor agonist, ameliorates experimental Parkinson’s disease in mice and Caenorhabditis elegans. Pharmacol. Res. 2021, 163, 105220. [Google Scholar] [CrossRef] [PubMed]
  205. Kasanga, E.A.; Han, Y.; Shifflet, M.K.; Navarrete, W.; McManus, R.; Parry, C.; Barahona, A.; Nejtek, V.A.; Manfredsson, F.P.; Kordower, J.H.; et al. Nigral-specific increase in ser31 phosphorylation compensates for tyrosine hydroxylase protein and nigrostriatal neuron loss: Implications for delaying parkinsonian signs. Exp. Neurol. 2023, 368, 114509. [Google Scholar] [CrossRef] [PubMed]
  206. David, V.; Besson, M.; Changeux, J.P.; Granon, S.; Cazala, P. Reinforcing effects of nicotine microinjections into the ventral tegmental area of mice: Dependence on cholinergic nicotinic and dopaminergic D1 receptors. Neuropharmacology 2006, 50, 1030–1040. [Google Scholar] [CrossRef]
  207. Ikemoto, S.; Qin, M.; Liu, Z.H. Primary reinforcing effects of nicotine are triggered from multiple regions both inside and outside the ventral tegmental area. J. Neurosci. 2006, 26, 723–730. [Google Scholar] [CrossRef]
  208. de Oliveira, A.R.; Reimer, A.E.; Brandão, M.L. Role of dopamine receptors in the ventral tegmental area in conditioned fear. Behav. Brain Res. 2009, 199, 271–277. [Google Scholar] [CrossRef] [PubMed]
  209. Cai, J.; Tong, Q. Anatomy and Function of Ventral Tegmental Area Glutamate Neurons. Front. Neural Circuits 2022, 16, 867053. [Google Scholar] [CrossRef] [PubMed]
  210. Hamamah, S.; Aghazarian, A.; Nazaryan, A.; Hajnal, A.; Covasa, M. Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling. Biomedicines 2022, 10, 436. [Google Scholar] [CrossRef] [PubMed]
  211. Kutlu, M.G.; Burke, D.; Slade, S.; Hall, B.J.; Rose, J.E.; Levin, E.D. Role of insular cortex D1 and D2 dopamine receptors in nicotine self-administration in rats. Behav. Brain Res. 2013, 256, 273–278. [Google Scholar] [CrossRef] [PubMed]
  212. Song, Y.; Chu, R.; Cao, F.; Wang, Y.; Liu, Y.; Cao, J.; Guo, Y.; Mi, W.; Tong, L. Dopaminergic Neurons in the Ventral Tegmental-Prelimbic Pathway Promote the Emergence of Rats from Sevoflurane Anesthesia. Neurosci. Bull. 2022, 38, 417–428. [Google Scholar] [CrossRef] [PubMed]
  213. Root, D.H.; Hoffman, A.F.; Good, C.H.; Zhang, S.; Gigante, E.; Lupica, C.R.; Morales, M. Norepinephrine activates dopamine D4 receptors in the rat lateral habenula. J. Neurosci. 2015, 35, 3460–3469. [Google Scholar] [CrossRef] [PubMed]
  214. Isaacson, S.H.; Hauser, R.A.; Pahwa, R.; Gray, D.; Duvvuri, S. Dopamine agonists in Parkinson’s disease: Impact of D1-like or D2-like dopamine receptor subtype selectivity and avenues for future treatment. Clin. Park. Relat. Disord. 2023, 9, 100212. [Google Scholar] [CrossRef] [PubMed]
  215. Mailman, R.B.; Yang, Y.; Huang, X. D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa. Eur. J. Pharmacol. 2021, 892, 173760. [Google Scholar] [CrossRef]
  216. Zhao, F.; Cheng, Z.; Piao, J.; Cui, R.; Li, B. Dopamine Receptors: Is It Possible to Become a Therapeutic Target for Depression? Front. Pharmacol. 2022, 13, 947785. [Google Scholar] [CrossRef]
  217. Svensson, K.A.; Heinz, B.A.; Schaus, J.M.; Beck, J.P.; Hao, J.; Krushinski, J.H.; Reinhard, M.R.; Cohen, M.P.; Hellman, S.L.; Getman, B.G.; et al. An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis. J. Pharmacol. Exp. Ther. 2017, 360, 117–128. [Google Scholar] [CrossRef]
  218. Riesenberg, R.; Werth, J.; Zhang, Y.; Duvvuri, S.; Gray, D. PF-06649751 efficacy and safety in early Parkinson’s disease: A randomized, placebo-controlled trial. Ther. Adv. Neurol. Disord. 2020, 13, 1756286420911296. [Google Scholar] [CrossRef]
  219. Young, D.; Popiolek, M.; Trapa, P.; Fonseca, K.R.; Brevard, J.; Gray, D.L.; Kozak, R. D1 Agonist Improved Movement of Parkinsonian Nonhuman Primates with Limited Dyskinesia Side Effects. ACS Chem. Neurosci. 2020, 11, 560–566. [Google Scholar] [CrossRef]
  220. Sohur, U.S.; Gray, D.L.; Duvvuri, S.; Zhang, Y.; Thayer, K.; Feng, G. Phase 1 Parkinson’s Disease Studies Show the Dopamine D1/D5 Agonist PF-06649751 is Safe and Well Tolerated. Neurol. Ther. 2018, 7, 307–319. [Google Scholar] [CrossRef]
  221. Balice-Gordon, R.; Honey, G.D.; Chatham, C.; Arce, E.; Duvvuri, S.; Naylor, M.G.; Liu, W.; Xie, Z.; DeMartinis, N.; Harel, B.T.; et al. A Neurofunctional Domains Approach to Evaluate D1/D5 Dopamine Receptor Partial Agonism on Cognition and Motivation in Healthy Volunteers With Low Working Memory Capacity. Int. J. Neuropsychopharmacol. 2020, 23, 287–299. [Google Scholar] [CrossRef]
  222. Huang, X.; Lewis, M.M.; Van Scoy, L.J.; De Jesus, S.; Eslinger, P.J.; Arnold, A.C.; Miller, A.J.; Fernandez-Mendoza, J.; Snyder, B.; Harrington, W.; et al. The D1/D5 Dopamine Partial Agonist PF-06412562 in Advanced-Stage Parkinson’s Disease: A Feasibility Study. J. Parkinsons Dis. 2020, 10, 1515–1527. [Google Scholar] [CrossRef]
  223. Papapetropoulos, S.; Liu, W.; Duvvuri, S.; Thayer, K.; Gray, D.L. Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson’s Disease following Oral Administration. Neurodegener. Dis. 2018, 18, 262–269. [Google Scholar] [CrossRef]
  224. Yang, P.; Knight, W.C.; Li, H.; Guo, Y.; Perlmutter, J.S.; Benzinger, T.L.S.; Morris, J.C.; Xu, J. Dopamine D1 + D3 receptor density may correlate with parkinson disease clinical features. Ann. Clin. Transl. Neurol. 2021, 8, 224–237. [Google Scholar] [CrossRef]
  225. Ptacek, R.; Kuzelova, H.; Stefano, G.B.; Raboch, J.; Kream, R.M. Targeted D4 dopamine receptors: Implications for drug discovery and therapeutic development. Curr. Drug Targets 2013, 14, 507–512. [Google Scholar] [CrossRef]
  226. Mohr, P.; Masopust, J.; Kopeček, M. Dopamine Receptor Partial Agonists: Do They Differ in Their Clinical Efficacy? Front. Psychiatry 2021, 12, 781946. [Google Scholar] [CrossRef]
  227. Keks, N.; Hope, J.; Schwartz, D.; McLennan, H.; Copolov, D.; Meadows, G. Comparative Tolerability of Dopamine D2/3 Receptor Partial Agonists for Schizophrenia. CNS Drugs 2020, 34, 473–507. [Google Scholar] [CrossRef] [PubMed]
  228. Kaczor, A.A.; Wróbel, T.M.; Bartuzi, D. Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis. Molecules 2022, 28, 178. [Google Scholar] [CrossRef] [PubMed]
  229. Basu, D.; Tian, Y.; Bhandari, J.; Jiang, J.R.; Hui, P.; Johnson, R.L.; Mishra, R.K. Effects of the dopamine D2 allosteric modulator, PAOPA, on the expression of GRK2, arrestin-3, ERK1/2, and on receptor internalization. PLoS ONE 2013, 8, e70736. [Google Scholar] [CrossRef] [PubMed]
Table 1. The major functions, localization, and physiological significance of dopamine D1, D2, D3, D4, and D5 receptors in the brain.
Table 1. The major functions, localization, and physiological significance of dopamine D1, D2, D3, D4, and D5 receptors in the brain.
SubtypesLocationResponsesRef.
D1-Like
Receptors		D1 (D1A and D1B)
Receptor		Predominantly in the striatum, nucleus accumbens, substantia nigra, olfactory bulb, and cortexStimulates adenylate cyclase, increasing intracellular cAMP levels[1,2,3,5,6,13,14,15,16,17,18,19]
D5 ReceptorBroadly distributed in the brain, including in the hippocampus, thalamus, striatum, nucleus accumbens, and amygdalaStimulates adenylate cyclase, increasing intracellular cAMP levels[1,4,5,20,21,22,23]
D2-Like
Receptors		D2 (D2S and D2L)
Receptor		Predominantly in the striatum, nucleus accumbens, and olfactory bulb; the hippocampus, amygdala, hypothalamus, and cortex at a lower levelInhibits adenylate cyclase, decreasing cAMP levels[6,7,8,9,10,24,25,26,27,28,29,30,31,32,33,34]
D3 ReceptorFound in the nucleus accumbens, insular cortex, amygdala, and hippocampusInhibits adenylate cyclase, decreasing cAMP levels[35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51]
D4 ReceptorLocated in the prefrontal cortex, hippocampus, amygdala, and striatumInhibits adenylate cyclase, decreasing cAMP levels[52,53,54,55,56,57,58]
Table 2. The distribution and major functions of dopamine D1–D5 receptors in the dorsal striatum and their implications for disorders.
Table 2. The distribution and major functions of dopamine D1–D5 receptors in the dorsal striatum and their implications for disorders.
SubtypesExpressionFunctionRelated DiseasesRef.
D1 receptorsDirect pathway medium spiny neurons (dMSNs)Facilitation of movement,
reward and reinforcement,
cognitive functions,
neuroplasticity		Motor disorders, including Parkinson’s disease,
Huntington’s disease,
schizophrenia, addictions		[5,13,36,84,85,93,95,96,99,100,101,102]
D2 receptorsIndirect pathway medium spiny neurons (iMSNs)Inhibition of movement,
modulation of reward,
neurotransmitter release,
motor learning		Motor disorders, including Parkinson’s disease,
Huntington’s disease,
schizophrenia, addictions		[9,36,84,85,91,93,95,96,99,100,101,102,103,104,105,106]
D3 receptorsCholinergic interneurons and iMSNsEmotional responses,
motivation,
cognitive functions		Addiction,
schizophrenia,
mood disorders		[36,38,46,83,84,85,99,100,101,107]
D4 receptorsGABAergic interneurons and dMSNsExecutive functions,
emotional processing,
response to novelty		Attention-deficit hyperactivity disorder (ADHD),
certain psychiatric conditions		[36,53,54,84,85,99,101,104]
D5 receptorsCholinergic and parvalbumin-positive interneurons, dMSNsModulation of motor activity and cognitive processesSchizophrenia,
cognitive dysfunction		[5,9,23,84,85,99,101]
Table 3. The distribution and major functions of dopamine D1–D5 receptors in the ventral striatum (nucleus accumbens and olfactory tubercle) and their implication for disorders.
Table 3. The distribution and major functions of dopamine D1–D5 receptors in the ventral striatum (nucleus accumbens and olfactory tubercle) and their implication for disorders.
SubtypesExpressionFunctionRelated DiseasesRef.
D1 receptorsPredominantly in the dMSNsRewards, motivation, and learning; olfaction and learningImplicated in addiction, ADHD, schizophrenia, and depression[1,6,14,36,52,85,99,100,106,107,117,121,122]
D2 receptorsPredominantly in the iMSNsRewards, pleasures, and addictions; olfaction, social behavior, and emotionLinked to Parkinson’s disease, addiction, schizophrenia[1,6,14,36,52,85,99,100,106,107,117,121,122]
D3 receptorsNucleus accumbens shell; large aspiny neuronFear, anxiety, and depression; olfaction and rewardsAssociated with addiction, depression, and schizophrenia[83,85,99,100,107,121]
D4 receptorsNucleus accumbens core; medium aspiny neuronAttention and motivation;
olfaction and attention		Linked with ADHD and schizophrenia[53,54,85,99,100,121]
D5 receptorsNucleus accumbens shell; dMSNsMemory and cognition;
olfaction and memory		Implicated in learning, memory, and cognitive disorders[23,85,99,100,121]
Table 4. The distribution and major functions of dopamine D1–D5 receptors in the prefrontal cortex and their implication for disorders.
Table 4. The distribution and major functions of dopamine D1–D5 receptors in the prefrontal cortex and their implication for disorders.
SubtypesPhysiological FunctionsRelated DiseasesRef.
D1 receptorsWorking memory maintenance, cognitive flexibility, executive functions, modulation of emotional responsesImplicated in cognitive deficits, schizophrenia[38,67,85,88,99,100,118,119,120,125,139]
D2 receptorsModulation of executive functions, inhibition of impulsive behavior, regulation of reward-related behaviors, influences on attention and motivationAssociated with ADHD, addiction, cognitive impairments[38,67,85,88,99,100,118,119,120,125,139]
D3 receptorsModulation of emotional responses, involvement in motivation and reward, potential role in addiction and dependenceImplicated in mood disorders, addiction[38,67,85,88,99,100,118,119,120,125]
D4 receptorsContribution to executive functions, role in emotional processing, response to novelty, implications in attention disordersLinked to ADHD, psychiatric impairments[67,85,88,99,100,118,119,120,125]
D5 receptorsModulation of cognitive processes, potential involvement in schizophreniaAssociated with cognitive impairments, schizophrenia[5,23,84,121]
Table 5. The distribution and major functions of dopamine D1–D5 receptors in the subthalamic nucleus and their implication for disorders.
Table 5. The distribution and major functions of dopamine D1–D5 receptors in the subthalamic nucleus and their implication for disorders.
SubtypesPhysiological FunctionsRelated DiseasesRef.
D1 receptorsModulation of thalamocortical activity; motor functions, regulation of neuronal activity, working memory, and cognitive flexibilityLinked to movement disorders such as Parkinson’s disease, dyskinesia, schizophrenia, and addiction[13,14,102,117,122,156,158]
D2 receptorsRegulates thalamic output; reward processing and motor controlAssociated with schizophrenia, Parkinson’s disease, addiction, depression[14,102,113,122,157,159,160]
D3 receptorsMediates thalamic inhibition, motivation, and emotional regulationImplications in schizophrenia, addiction, depression, anxiety[42,83,100,107,161,162]
D4 receptorsInfluences thalamic gating, novelty seeking, and impulsivityImplications in schizophrenia, ADHD, addiction[67,150,155,163]
D5 receptorsEnhances thalamocortical transmission, learning, and memoryImplication in schizophrenia, Parkinson’s disease, Alzheimer’s disease[20,67,155,156,163]
Table 6. Major functions of dopamine D1–D5 receptors in the amygdala and their implication for disorders.
Table 6. Major functions of dopamine D1–D5 receptors in the amygdala and their implication for disorders.
SubtypesPhysiological FunctionsRelated DiseasesRef.
D1 receptorsModulation of emotional responses, fear conditioning, synaptic plasticity
Facilitates neuronal plasticity, which is necessary for fear conditioning and fear elimination		Dysfunctions linked to mood disorders, anxiety, and fear-related pathologies[3,14,57,117,121,122,158,164,166,167]
D2 receptorsRegulation of emotional responses and reinforcement learning
Suppresses neuronal plasticity, which is necessary for fear conditioning and fear elimination		Altered expression associated with mood disorders, addictive behaviors, anxiety[14,28,38,57,122,166,167]
D3 receptorsModulation of emotional responses, motivation, and reward, potential role in addiction and dependencePotential involvement in mood disorders, addictive behaviors, anxiety disorders[38,41,57,67,83,107,168]
D4 receptorsContribution to emotional processing, role in response to novelty, implications in attention and cognitive tasksADHD, schizophrenia, depression[55,57,67,169]
D5 receptorsModulation of emotional responses, involvement in cognitive processes, potential role in schizophreniaAlzheimer’s disease, depression, drug abuse[23,57,121,164,167]
Table 8. Major functions of dopamine D1–D5 receptors in the substantia nigra (SN) and their implication for disorders.
Table 8. Major functions of dopamine D1–D5 receptors in the substantia nigra (SN) and their implication for disorders.
SubtypesPhysiological FunctionsRelated DiseasesRef.
D1 receptorsPositive modulation of motor coordination, influencing cognitive functionsDysfunctions linked to movement disorders like Parkinson’s disease, motor impairments, and potentially addictive behaviors[15,22,84,93,101,125,189,191,192,193,194]
D2 receptorsInhibition of excessive movement,
control of reward-related behaviors
involvement in motor skill learning		Altered expression associated with movement disorders, such as Parkinson’s disease, and some neuropsychiatric conditions[22,91,93,101,125,140,194,195]
D3 receptorsModulation of emotional responses
Regulation of cognitive functions		Potential implications in movement disorders[38,42,49,83,101,125]
D4 receptorsContribution to executive functions
Role in response to novelty		Parkinson’s disease, motor impairments[53,54,67,84,101]
D5 receptorsModulation of motor activity
Regulation of cognitive functions		Parkinson’s disease, motor impairments[4,20,22,23,101]
Table 9. Major functions of dopamine D1–D5 receptors in the ventral tegmental area (VTA) and their implication for disorders.
Table 9. Major functions of dopamine D1–D5 receptors in the ventral tegmental area (VTA) and their implication for disorders.
SubtypesPhysiological FunctionsRelated DiseasesRef.
D1 receptorsRegulation of reward-related behaviors, control of motivation and reinforcement, contribution to emotional responsesDysfunctions may contribute to addictive behaviors, mood disorders, and cognitive impairments[1,6,13,102,116,125,210,211,212]
D2 receptorsModulation of aversive responses, regulation of neurotransmitter release, contribution to motor learning and adaptationAltered expression linked to addiction, schizophrenia, and potentially motor-related disorders[1,6,116,125,210,211]
D3 receptorsInfluence on motivation and reward processing, potential role in drug addiction and dependenceImplications in addiction and reward-related disorders[38,67,125,210]
D4 receptorsInvolved in regulating dopamine pathways, potential role in motivationPotential involvement in motivation and reward-related disorders, depression[54,67,150,210,213]
D5 receptorsModulates neurotransmission, influences motor functions and cognitive processesAddiction and cognitive impairments, depression[4,20,23,67,210]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Kawahata, I.; Finkelstein, D.I.; Fukunaga, K. Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease. Receptors 2024, 3, 155-181. https://doi.org/10.3390/receptors3020009

AMA Style

Kawahata I, Finkelstein DI, Fukunaga K. Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease. Receptors. 2024; 3(2):155-181. https://doi.org/10.3390/receptors3020009

Chicago/Turabian Style

Kawahata, Ichiro, David I. Finkelstein, and Kohji Fukunaga. 2024. "Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease" Receptors 3, no. 2: 155-181. https://doi.org/10.3390/receptors3020009

APA Style

Kawahata, I., Finkelstein, D. I., & Fukunaga, K. (2024). Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease. Receptors, 3(2), 155-181. https://doi.org/10.3390/receptors3020009

Article Metrics

Back to TopTop