Search Results (498)

Ethanol produces both aversive and rewarding effects during the intoxication phase; however, the receptor-specific pharmacological mechanisms and neural circuits underlying this paradox remain poorly defined. The present study investigated how dopamine D2 and GABA(A) receptor systems differentially regulate ethanol-induced aversion and reward at behavioral and neural circuit levels. Rats received systemic administration of the dopamine D2 receptor agonist apomorphine, the GABA(A) receptor agonist muscimol, or the GABA(A) receptor antagonist bicuculline prior to ethanol conditioning. Ethanol-induced aversion and reward were assessed using conditioned taste aversion (CTA) and conditioned place preference (CPP), respectively, and neural activation was examined using c-Fos immunohistochemistry in the medial prefrontal cortex, amygdala, and hippocampus. Apomorphine potentiated ethanol-induced CTA while suppressing ethanol-induced CPP. In contrast, bicuculline attenuated ethanol-induced CTA and abolished ethanol-induced CPP, whereas muscimol enhanced aversive CTA and converted ethanol-induced CPP into conditioned place aversion. During CTA, apomorphine predominantly changed c-Fos expression in amygdalar and hippocampal subregions, whereas GABA(A) receptor manipulation altered activity within the medial prefrontal–amygdala–hippocampal network. During CPP, dopamine D2 receptor activation enhanced neural activity in the medial prefrontal cortex and hippocampus while suppressing central amygdala activity, whereas GABA(A) receptor modulation reduced prefrontal activation and enhanced amygdalar and hippocampal engagement. Altogether, these findings reveal receptor-specific and context-dependent corticolimbic mechanisms through which dopamine D2 and GABA(A) receptors differentially regulate ethanol-induced aversive and rewarding states during acute intoxication. Full article

Growth hormone-releasing hormone receptor 1a (GHS-R1a) is a key G protein-coupled receptor (GPCR) governing feeding and energy homeostasis. Accumulating evidence shows that GHS-R1a forms functional heterodimers with multiple metabolic-related GPCRs, including dopamine 2 receptor (D2R), melanocortin 3 receptor (MC3R), 5-hydroxytryptamine 2c receptor (5-HT2cR), orexin receptor 1 (OX1R) and cannabinoid receptor 1 (CB1R). These heterodimers undergo distinct signal transduction reprogramming, generating novel physiological effects that are not observed with individual receptors: for instance, GHS-R1a/D2R mediates an atypical calcium signaling pathway to regulate appetite, while GHS-R1a/5-HT2cR antagonizes ghrelin-induced orexigenic effects. Meanwhile, diverse detection techniques, including co-immunoprecipitation and fluorescence resonance energy transfer, have been developed to identify and validate GHS-R1a heterodimerization, laying a solid foundation for mechanistic research. This review systematically summarizes the molecular mechanisms of GHS-R1a heterodimer formation, the characteristic signal regulation patterns of different heterodimers, and their specific regulatory roles in feeding circuits. Furthermore, we discuss the existing research gaps in this field, such as the lack of in vivo detection methods for heterodimers and the unclear structural basis of dimerization. Finally, we highlight the potential of targeting specific GHS-R1a heterodimers as a novel therapeutic strategy for obesity and anorexia, providing new directions for future pharmaceutical development and clinical translation. Full article

The hypothesis that Group A beta-haemolytic Streptococcus (GAS) triggers an autoimmune cascade targeting basal ganglia dopaminergic circuits—producing obsessive–compulsive disorder (OCD), tic disorders, or chorea depending on the receptor subtype involved—is biologically compelling and supported by emerging molecular evidence. Yet PANDAS has remained a diagnostic conundrum since its original description in 1998, with ongoing uncertainty surrounding diagnostic criteria, the interpretation of streptococcal serology, and the distinction from primary neurodevelopmental disorders. This study aimed to review the diagnostic challenges of PANDAS, with focus on streptococcal serology interpretation, advances in dopamine receptor autoantibody biology, the genetic epidemiology of primary tic disorders, and the differential diagnosis of acute neuropsychiatric presentations in children. A structured narrative review was conducted using PubMed, MEDLINE, EMBASE, and the Cochrane Library for publications from 1998 to early 2025 addressing PANDAS, PANS, streptococcal antibodies, childhood movement disorders, autoimmune encephalitis, and the genetics of tic disorders. No currently available biomarker—including ASO, anti-DNase B, anti-basal-ganglia antibodies, or the Cunningham Panel—has demonstrated adequate individual-level diagnostic accuracy for PANDAS. Emerging molecular evidence identifies anti-D1R autoantibodies, acting via G protein-and beta-arrestin-mediated signalling, as candidate biomarkers for PANDAS/PANS neuropsychiatric phenotypes, and anti-D2R autoantibodies for Sydenham chorea movement phenotypes; independent replication in unselected populations is required. Primary tic disorders carry heritability estimates of 50–80% and first-degree familial risk ratios of approximately 18-fold in large population-based cohorts. Prospective blinded studies have not demonstrated a consistent population-level association between GAS infections and tic or OCD exacerbations: PANDAS and PANS remain diagnoses of exclusion. The high background prevalence of both GAS exposure and primary neurodevelopmental disorders in overlapping paediatric age ranges creates conditions for incidental temporal co-occurrence. In the absence of validated molecular biomarkers, diagnostic imprecision carries direct clinical consequences: children may be exposed to treatments with significant risk profiles—including IVIG, plasma exchange, and prolonged antibiotic prophylaxis—while evidence-based therapies are delayed. A stepwise diagnostic approach incorporating the full differential diagnosis is both an epistemological and a patient safety imperative. Full article

Tardive dyskinesia (TD) is a persistent hyperkinetic movement disorder associated with prolonged dopamine D2 receptor blockade, particularly during chronic haloperidol (HP) exposure. Emerging evidence suggests that TD-like pathology is sustained by an interconnected redox–mitochondrial–inflammatory network within striatal circuits; however, the regulatory architecture of this network remains incompletely defined. Hyperoside (HS), a flavonol glycoside with cytoprotective properties, has been implicated in cellular stress-response modulation, yet its role in antipsychotic-induced motor dysfunction remains unclear. In this study, a six-group mechanistic design was employed in which rats received HP (1 mg/kg, i.p., 21 days) to induce TD-like orofacial dyskinesia (OD), quantified by vacuous chewing movements (VCMs) and tongue protrusions (TPs). HS (30 mg/kg, i.p.) was administered alone or in combination with HP, with or without pharmacological inhibition of nuclear factor erythroid 2–related factor 2 (Nrf2) using ML385. HP exposure induced progressive dyskinetic behavior accompanied by oxidative and nitrosative stress, mitochondrial dysfunction, increased pro-inflammatory cytokines, and elevated caspase-3 activity in the striatum. HS significantly attenuated behavioral abnormalities while restoring redox balance, preserving mitochondrial enzyme activities, and reducing inflammatory and apoptotic signaling. Notably, Nrf2 inhibition intensified molecular pathology without proportionally worsening behavioral outcomes, indicating a dissociation between biochemical vulnerability and overt motor expression. Furthermore, ML385 markedly attenuated HS-mediated protection across multiple endpoints. Collectively, these findings support a potential protective role for Nrf2-related regulatory mechanisms in limiting network destabilization in TD-like pathology, while highlighting the importance of integrated stress-response pathways in modulating disease progression. Full article

Memory is generally thought to be stored within centralized neural circuits. However, whether learned behaviors can persist in the absence of a brain remains unresolved. Planaria (Girardia spp.) possess a primitive cephalic ganglion and a remarkable capacity for regeneration, providing a unique system to examine non-cephalic memory retention. The primary aim of this study was to determine whether sucrose-induced conditioned place preference (CPP) is retained in posterior, brainless planarian fragments. Planaria were trained using a Pavlovian conditioning paradigm in which an initially unpreferred surface was paired with a 10% sucrose solution, resulting in a robust shift in surface preference. Following amputation, anterior fragments containing the cephalic ganglion as well as posterior fragments lacking the brain preserved the conditioned preference, demonstrating that reward-associated memory is stored even outside the cephalic nervous system. As a secondary objective, we examined the role of dopaminergic reinforcement using a D1 dopamine receptor antagonist during training. While antagonist-treated planaria failed to develop a CPP, posterior fragments from these amputated planaria likewise showed no conditioned preference, indicating that dopamine-dependent signaling is essential for sucrose-associated memory formation across the body. These results provide support for the hypothesis that reward-associated memory in planaria is distributed beyond the brain and can be modulated by dopaminergic pathways, highlighting the utility of this model for exploring fundamental mechanisms of reward, memory, and potential pharmacological interventions. Full article

Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Methods: Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. Results: CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Conclusions: Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers. Full article

Natural products represent an important reservoir for GPCR ligand discovery. In this study, we established an integrated workflow combining virtual screening, biophysical validation, functional signaling assays, and transcriptomic profiling to identify reticuline, a dopamine-derived intermediate from the genus of Stephania, as a potential agonist of dopamine D5 receptor (D5R). Molecular docking revealed that most dopamine-derived compounds along the BIA synthetic pathway exhibit predicted binding affinities for the D5R that are lower than that of dopamine. As expected, the reticuline–D5R complex has a favorable predicted binding affinity of −7.9 kcal/mol. As for binding validation, direct interaction between reticuline and D5R was experimentally confirmed using cell membrane chromatography (CMC) and bio-layer interferometry (BLI), yielding a dissociation constant of 1.07 μM. cAMP assay demonstrated that reticuline activates D5R-mediated Gs-cAMP increasement in a concentration-responsive manner, which exhibits agonist-like activity with an EC₅₀ value of 0.07 μM. The transcriptomic profiling further revealed that reticuline treatment induces transcriptional reprogramming in D5R-overexpressing cells, with enrichment of pathways related to ribosome biogenesis, mitochondrial oxidative phosphorylation, and neurodegenerative diseases. In summary, this study demonstrates that reticuline acts as a potential D5R agonist and highlights a systematic natural product-GPCR discovery strategy integrating computational prediction, experimental validation, and transcriptome-level mechanistic exploration. Full article

Hypertension continues to be a major global public health challenge. Dopamine generated in the kidney is a vital coordinator of sodium homeostasis and blood pressure control. Dopamine exerts its effects by activating its receptors, which are divided into the D₁-like receptor family (D₁R and D₅R) and the D₂-like receptor family (D₂R, D₃R, and D₄R). All five dopamine receptor subtypes are differentially expressed along the nephron. Dopamine receptors inhibit the activities and/or expression of renal tubular sodium transporters/exchangers/channels, decrease renal oxidative stress, and interact with other receptors, including angiotensin II receptors. Many studies have demonstrated that renal dopamine receptors play an important role in the regulation of blood pressure. The germline deletion or renal-selective silencing of any of the five dopamine receptor subtypes may impair sodium excretion and increase blood pressure. In addition, renal dopamine receptor expression and/or function are regulated by some factors such as G protein-coupled receptor kinases, oxidative stress, and sorting nexins. In this article, we summarize the role of each dopamine receptor subtype in the pathogenesis of hypertension and discuss the potential regulatory mechanisms of their expression and function. These may lead to the development of novel therapeutic approaches to the prevention and treatment of hypertension. Full article

Background: Biological sex contributes to variability in drug metabolism, receptor sensitivity, and susceptibility to adverse drug reactions (ADRs). Despite this, dosing recommendations for selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics (SGAs) are still largely sex-neutral. This systematic review examines sex-related differences in pharmacokinetics (PK), pharmacodynamics (PD), and safety outcomes, with the aim of clarifying their potential implications for personalized psychopharmacology. Methods: A systematic search of PubMed was conducted for studies published between January 2010 and March 2026. The strategy combined MeSH terms and free-text keywords related to SSRIs, SGAs, sex differences, pharmacokinetics, pharmacodynamics, and ADRs. Two independent reviewers performed study selection and data extraction. Studies reporting sex-stratified PK, PD, or safety outcomes in humans were included. Owing to methodological heterogeneity, results were synthesized narratively. Results: Twenty-seven studies met the inclusion criteria. Overall, the evidence indicates clinically meaningful sex-related differences in psychotropic drug exposure and response. Women more frequently exhibited higher dose-adjusted serum concentrations, particularly for risperidone and some SSRIs, with age-related increases more evident in females. Pharmacodynamic findings suggest that women may reach comparable dopamine D2 receptor occupancy at lower olanzapine doses. Pharmacovigilance analyses revealed sex-specific adverse event patterns, including greater reporting of endocrine-related effects and QT prolongation in women. Conclusions: Sex influences psychotropic drug exposure, pharmacodynamic sensitivity, and safety profiles in ways that may be clinically relevant. Integrating sex-aware considerations into dosing strategies could improve therapeutic precision and reduce adverse outcomes, reinforcing the importance of sex as a key variable in personalized psychiatric care. Full article

Background/Objectives: Salidroside, a bioactive phenylethanol glycoside primarily derived from Rhodiola rosea, and its major in vivo metabolite tyrosol exhibit diverse pharmacological activities. However, their direct molecular targets remain poorly defined. Methods: In the present study, an integrated strategy combining transcriptomic profiling, Connectivity Map (CMap) analysis, and multi-level experimental validation was employed. Transcriptomic signatures derived from A549 cells treated with salidroside or tyrosol were queried against the CMap database. Molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assays (CETSA) were performed to predict and validate binding interactions. Functional validation was performed in SH-SY5Y cells. The phosphorylation level of extracellular signal-regulated kinase (ERK), a downstream signaling event of dopamine D2 receptor (DRD2), was detected after salidroside and tyrosol treatment. DRD2 antagonist sulpiride pre-intervention and small interfering RNA (siRNA)-mediated DRD2 knockdown were conducted to verify the receptor dependence of the compounds’ effects. Results: CMap analysis revealed that the transcriptomic signatures of salidroside and tyrosol showed significant similarity to known DRD2 modulators. Molecular docking predicted potential binding interactions between the two compounds and DRD2, which was confirmed by SPR and CETSA to be direct physical binding. Functional studies showed that both compounds rapidly induced DRD2 downstream ERK phosphorylation in SH-SY5Y cells; this effect was abrogated by sulpiride or DRD2 knockdown, indicating DRD2-dependent signaling activation. Conclusions: These findings identify DRD2 as a direct molecular target of salidroside and tyrosol and provide mechanistic insight into their dopaminergic regulatory effects. This study highlights the utility of CMap-guided target discovery combined with rigorous experimental validation for elucidating the molecular mechanisms of natural products. Full article

Background: The term dyskinesia describes involuntary movements of the face, body and extremities. Frequently, they appear following and in relation with prior oral long-lasting and high-dose levodopa therapy in Parkinson’s disease patients. Onset of these motion sequences causes patient distress and caregiver embarrassment with declined quality of life. Continuity of nigrostriatal postsynaptic dopamine receptor stimulation delays occurrence of dyskinesia. A pulsatile pattern with temporary too high dopamine receptor excitation promotes manifestation of dyskinesia. Methods: This narrative review describes past pharmacologic approaches for therapy of dyskinesia, such as the principle of continuous dopamine receptor stimulation. Discussion and Conclusions: Novel concepts were tested. They influenced neurotransmission of serotonin and altered stimulation of dopamine receptor subtypes. The translation of successful experimental research outcomes into valuable clinical trial results with consecutive approval of drugs with a new mode of action under the indication “antidyskinetic” repeatedly failed. An exception is the open-channel blocker of the N-methyl-D-aspartate receptor and dopamine reuptake inhibitor amantadine with its moderate dyskinesia-reducing effects, particularly in its extended-release formulation. This antiviral compound also improves impaired motor behavior and reduces “OFF” intervals. Therefore, amantadine is currently experiencing a certain resurgence in regions where its extended-release formulations are marketed for therapy of levodopa-induced dyskinesia. Full article

Parkinson’s disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons, leading to motor dysfunction and compensatory postsynaptic dopamine receptor alterations. Valproic acid (VPA), a histone deacetylase inhibitor, has shown neuroprotective properties; however, its dose-dependent effects on dopaminergic integrity and dopamine D2 receptor (D2R) regulation remain unclear. Adult male Wistar rats received VPA (200 or 400 mg/kg, p.o.) or vehicle for 20 days prior to unilateral 6-hydroxydopamine (6-OHDA) lesioning. Motor performance was evaluated using the beam balance test, exploratory behavior in the open field, striatal dopamine levels by PLC-electrochemical detection, and D2R protein expression by Western blot. The 6-OHDA lesion induced marked motor deficits, reduced striatal dopamine content, and significantly increased D2R expression. VPA at 200 mg/kg produced only minor, non-significant effects. In contrast, VPA at 400 mg/kg preserved motor performance, attenuated dopamine depletion, and normalized striatal D2R expression. These findings demonstrate a clear dose-dependent neuroprotective effect of VPA and indicate that stabilization of postsynaptic D2R expression accompanies preservation of dopaminergic terminals in the 6-OHDA rat model. Full article

Dopamine is one of the most important neurotransmitters for regulating retinal function and adjusting vision to the diurnal cycle. It exerts its regulatory effects, in part, through the cAMP pathway. Previous studies have demonstrated that dopamine affects phototransduction in amphibian rods, and that elevated intracellular levels of cAMP modulate the function of vertebrate rods and cones. Lamprey, the most primitive vertebrate, could be valuable for studying the evolution of dopamine regulatory loops in the retina. We examined whether the photoresponse properties of long (cone-like) and short (rod-like) photoreceptors in the river lamprey could be regulated by dopamine via the cAMP pathway. Using suction pipette recording, we demonstrated that forskolin-induced elevation of cAMP has no effect on long or short photoreceptors. At the same time, dopamine modifies the photoresponse properties of long, but not short, photoreceptors at high, potentially non-physiological concentrations. Immunohistochemical analysis of the lamprey retina revealed the expression of both D1 and D2 dopamine receptors in lamprey photoreceptors; however, their distribution differs from jawed vertebrates. Taken together, our results suggest that, in lampreys, dopamine does not regulate photoreceptor sensitivity to light in the circadian rhythm, but, rather, adjusts other retinal functions based on widespread distribution of its receptors. Full article

Extensive research in laboratory rodents has shown that novelty exposure enhances the consolidation of memories for preceding or following low-arousal events by elevating dopamine release in the dorsal hippocampus (dHipp). Additionally, numerous studies have demonstrated that post-encoding noradrenergic activation of the basolateral amygdala (BLA) can also enhance memory consolidation in dHipp. Since the BLA is most active during emotionally arousing or stress-related situations, it was suggested that this nuclear complex mediates the effects of emotional salience on memory consolidation. However, it is presently unknown whether the reinforcement of memory storage in dHipp induced by novel and arousing environmental conditions results from the interaction between these two modulatory systems. To test the hypothesis of a functional interaction between dopaminergic and noradrenergic systems, this study assessed their combined effects on a low-arousal object-location (OL) task. Rats received post-training intra-BLA infusions of vehicle or clenbuterol (Clen), a selective β-adrenoceptor agonist. Novelty-induced dopamine release in the dHipp was enhanced by omitting habituation prior to training, and the contribution of dopamine signaling was further evaluated using pre-infusion administration of the D1/D5 receptor antagonist SCH 23390. The distribution of two important proteins for memory processing, namely the activity-regulated cytoskeleton-associated protein (Arc) and the phosphorylated form of the transcription factor, cAMP-response element-binding protein (pCREB) in the dHipp, was explored in a subset of rats perfused 60 min after the training phase. Stimulation of the BLA significantly increased the number of Arc- and pCREB-positive cells in several dHipp areas. The preceding application of SCH 23390, however, substantially decreased these effects in the same areas, i.e., the dentate gyrus (DG), CA2, and CA1 subregions for pCREB, and the CA3b, CA3c, CA2, and CA1 subregions for Arc. This interaction is considered essential for the initial stages of memory consolidation. The obtained results indicate the presence of a region-specific interaction between BLA modulatory inputs and intrahippocampal dopaminergic transmission, the mechanisms of which remain to be elucidated. Full article