Search Results (53)

Background: Personality traits, particularly Conscientiousness, are recognised as crucial psychological factors contributing to success in elite-level athletes. Emerging evidence suggests that individual differences in these traits are influenced by environmental exposure and genetic variation, especially within the dopaminergic system. The DRD2 promoter polymorphism rs1799732, which affects dopamine D2 receptor expression, may modulate goal-directed behaviour and self-regulation traits. Methods: This study included 323 participants (141 elite mixed martial arts (MMA) athletes and 182 non-athlete controls). Participants completed the NEO Five-Factor Inventory (NEO-FFI). Genotyping for the DRD2 rs1799732 polymorphism was conducted using real-time PCR. Group comparisons and two-way ANOVA were used to assess genotype–phenotype associations and gene × environment interactions. Results: Athletes scored significantly higher on Conscientiousness than controls. A significant main effect of the DRD2 rs1799732 genotype and a genotype × group interaction were observed for Conscientiousness. Specifically, athletes with the ins/ins genotype exhibited the highest levels of Conscientiousness, whereas individuals with the del/del genotype showed the lowest scores. No significant associations were found for other personality traits. Conclusions: These findings suggest that the DRD2 promoter polymorphism rs1799732 moderates the expression of Conscientiousness, particularly under the structured and demanding conditions experienced by elite athletes. Our results support a gene × environment interaction model, highlighting the importance of considering genetic predispositions in high-performance environments. These insights may inform personalised psychological support strategies tailored to athletes’ genetic profiles, enhancing motivation, self-regulation and long-term athletic development. Full article

Prenatal cannabis exposure (PCE) has been associated with altered prefrontal cortex (PFC) activity and connectivity in adulthood, potentially increasing the risk of psychopathology later in life. This risk is thought to involve a complex interplay between the endocannabinoid and dopaminergic systems. We investigated the transcriptional regulation of genes associated with these systems in an animal model of PCE during adolescence, focusing on DNA methylation and specific microRNAs (miRNAs). Our study revealed increased mRNA levels of dopamine D1 and D2 receptors (Drd1 and Drd2) in the PFC, with a notable effect on Drd2 in male offspring. Notably, we observed a consistent reduction in Drd2 DNA methylation levels in PCE male rats. Both Drd1 and Drd2 expressions were regulated by selective miRNAs. Accordingly, we found changes in the excitability of PFC pyramidal neurons in male adolescent PCE offspring, along with alterations in the Netrin-1/DCC guidance cue system. Our findings highlight PCE-induced modifications of the PFC dopaminergic system while maintaining stable gene expression of the endocannabinoid system in male offspring. Changes in this complex interaction during sensitive developmental periods like adolescence might lead to sex-dependent divergent behavioral outcomes induced by PCE. Full article

Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and DRD2- and DRD3-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and Q23-DRD3-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and Q74-DRD3-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and DRD3-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients. Full article

Background/Objectives: Montelukast (MLK), a leukotriene receptor antagonist, has been associated with neuropsychiatric side effects. This study aimed to rationally modify MLK’s structure to reduce these risks by optimizing its interactions with dopamine D2 (DRD2) and serotonin 5-HT1A receptors using computational molecular simulation techniques. Methods: A library of MLK derivatives was designed and screened using structural similarity analysis, molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations, and ADME-Tox predictions. Structural similarity analysis, based on Tanimoto coefficient fingerprinting, compared MLK derivatives to known neuropsychiatric drugs. Docking was performed to assess initial receptor binding, followed by 100 ns MD simulations to evaluate binding stability. MM/PBSA calculations quantified binding affinities, while ADME-Tox profiling predicted pharmacokinetic and toxicity risks. Results: Several MLK derivatives showed enhanced DRD2 and 5-HT1A binding. MLK_MOD-42 and MLK_MOD-43 emerged as the most promising candidates, exhibiting MM/PBSA binding free energies of −31.92 ± 2.54 kcal/mol and −27.37 ± 2.22 kcal/mol for DRD2 and −30.22 ± 2.29 kcal/mol and −28.19 ± 2.14 kcal/mol for 5-HT1A, respectively. Structural similarity analysis confirmed that these derivatives share key pharmacophoric features with atypical antipsychotics and anxiolytics. However, off-target interactions were not assessed, which may influence their overall safety profile. ADME-Tox analysis predicted improved oral bioavailability and lower neurotoxicity risks. Conclusions: MLK_MOD-42 and MLK_MOD-43 exhibit optimized receptor interactions and enhanced pharmacokinetics, suggesting potential neuropsychiatric applications. However, their safety and efficacy remain to be validated through in vitro and in vivo studies. Until such validation is performed, these derivatives should be considered as promising candidates with optimized receptor binding rather than confirmed safer alternatives. Full article

Methamphetamine (METH) use disorder (MUD) is a public health catastrophe. Herein, we used a METH self-administration model to assess behavioral responses to the dopamine receptor D1 (DRD1) antagonist, SCH23390. Differential gene expression was measured in the dorsal striatum after a 30-day withdrawal from METH. SCH23390 administration reduced METH taking in all animals. Shock Resistant (SR) rats showed greater incubation of METH seeking, which was correlated with increased Creb1, Cbp, and JunD mRNA expression. Cytoplasmic polyadenylation element binding protein 4 (Cpeb4) mRNA levels were increased in shock-sensitive (SS) rats. SS rats also showed increased protein levels for cleavage and polyadenylation specificity factor (CPSF) and germ line development 2 (GLD2) that are CPEB4-interacting proteins. Interestingly, GLD2-regulated GLUN2A mRNA and its protein showed increased expression in the shock-sensitive rats. Taken together, these observations identified CPEB4-regulated molecular mechanisms acting via NMDA GLUN2A receptors as potential targets for the treatment of METH use disorder. Full article

Background: Dopamine (DA) is an important neurotransmitter that is widely present in the central nervous system. DA plays a crucial regulatory role in mammalian emotion, endocrine function, and reproduction through the activation of dopamine receptors. We compared the transcriptomes of hypothalamic tissues from Kazakh sheep during the nonbreeding season of anoestrus and during the nutrient-induced nonbreeding season of oestrus. Our research findings suggest that the dopamine receptor D1 (DRD1) gene may be a candidate gene for the regulation of sheep oestrus. However, the underlying mechanism through which DRD1 regulates sheep oestrus is still poorly understood. Methods: In the present study, the expression of DRD1 mRNA in the hypothalamus of oestrous Kazakh sheep was significantly greater than that in the anoestrous phase. Immunohistochemical staining revealed that DRD1 was more widely expressed in hypothalamic tissue and was more highly expressed during oestrus than during anoestrus. Hypothalamic neuron experiments further indicated that DRD1 affects the expression of GnRH through dopamine synapses and calcium signalling pathways. Results: moreover, the overexpression of the DRD1 gene promoted the secretion of GnRH, while knocking down the DRD1 gene reduced the secretion of GnRH. Conclusions: The present study revealed that the DRD1 gene plays a crucial regulatory role in the secretion of the hormone GnRH in the hypothalamus of Kazakh sheep. Full article

Valerian possesses a multitude of pharmacological effects, including sedative and hypnotic properties, antihypertensive effects, antibacterial activity, and liver protection. Insomnia, one of the most prevalent disorders in contemporary society, significantly impacts people’s daily lives. This study aims to explore the anti-insomnia effects of valerian volatile oil (VVO) and investigate its potential mechanism of action through chemical analysis, network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation. Through gas chromatography–mass spectrometry (GC-MS) analysis and drug-likeness screening, we identified 38 active compounds. Network pharmacology studies revealed that these 38 compounds might affect 103 targets associated with insomnia, such as monoamine oxidase B (MAOB), dopamine receptor D2 (DRD2), monoamine oxidase A (MAOA), interleukin 1β (IL1B), solute carrier family 6 member 4 (SLC6A4), prostaglandin-endoperoxide synthase 2 (PTGS2), and 5-hydroxytryptamine receptor 2A (HTR2A), which contribute to regulating the neuroactive ligand–receptor interaction, 5-hydroxytryptaminergic synapse, and calcium signaling pathways. The results of the molecular dynamics simulations indicated that bis[(6,6-dimethyl-3-bicyclo[3.1.1]hept-2-enyl)methyl] (E)-but-2-enedioate exhibited a stabilizing interaction with MAOB. The animal studies demonstrated that gavage administration of a high dose (100 mg/kg) of VVO significantly diminished autonomous activity, decreased sleep latency, and extended sleep duration in mice. Furthermore, the results of the Western blot experiment indicated that VVO interacts with MAOB, resulting in decreased expression levels of MAOB in the cerebral cortex. This study demonstrates the protective mechanism of VVO against insomnia through chemical analysis, network pharmacology, and experimental validation and extends the possible applications of VVO, which is a potential therapeutic ingredient for use in insomnia treatment. Full article

G protein-coupled receptors (GPCRs) are essential cell surface proteins involved in transducing extracellular signals into intracellular responses, regulating various physiological processes. This study validated the use of the Tango assay, a sensitive method for detecting GPCR activation, in Drosophila Schneider 2 (S2) cells, focusing on the human Dopamine Receptor D4 (DRD4). Plasmids encoding the LexA-tagged human DRD4 receptor and a luciferase reporter were co-transfected into Drosophila S2 cells and stimulated with dopamine. Receptor activation was measured by quantifying the luciferase activity. The system showed high specificity for dopamine, with no activation in response to octopamine, a non-ligand for DRD4. Furthermore, the system effectively detects activation by a novel compound. These results demonstrate that Drosophila S2 cells, coupled with the Tango assay, provide a viable model for studying human GPCR function and ligand specificity. This system enables the rapid screening of potential GPCR ligands in a cost-effective cellular model. Full article

Prolactinomas are commonly treated with dopamine receptor agonists (DAs), such as bromocriptine (BRC) and cabergoline (CAB). However, 10–30% of patients exhibit resistance to DA therapies. DA resistance is largely associated with reduced dopamine D2 receptor (DRD2) expression, potentially regulated by epigenetic modifications, though the underlying mechanisms are still unclear. Clinical samples were assessed for p300 expression. MMQ and AtT-20 cells were engineered to overexpress either wild-type p300 or a histone acetyltransferase (HAT) domain-mutant form of p300. Mechanistic studies included cell proliferation assays, flow cytometry, immunohistochemistry, immunofluorescence, co-immunoprecipitation, chromatin immunoprecipitation followed by quantitative PCR, reverse transcription quantitative PCR, and Western blotting. Additionally, an in vivo nude mouse xenograft model was used to confirm the in vitro findings. DAs downregulated p300 through the cAMP-PKA-CREB pathway. Activation of the HAT domain of p300 increased H3K18/27 acetylation, promoted DRD2 transcription, and worked synergistically with DA to exert anti-tumor effects both in vitro and in vivo. Tanshinone IIA (Tan IIA) upregulated p300 and DRD2, enhancing the therapeutic efficacy of BRC. These findings highlight the role of p300 in regulating DRD2 transcription in DA-resistant prolactinomas. Combining Tan IIA with BRC may offer a promising strategy to overcome DA resistance. Full article

The TaqIA polymorphism is a marker of both the Ankyrin Repeat and Kinase Domain containing I gene (ANKK1) encoding a RIP-kinase, and the DRD2 gene for the dopamine receptor D2. Despite a large number of studies of TaqIA in addictions and other psychiatric disorders, there is difficulty in interpreting this genetic phenomenon due to the lack of knowledge about ANKK1 function. In SH-SY5Y neuroblastoma models, we show that ANKK1 interacts with the synapse protein FERM ARH/RhoGEF and Pleckstrin Domain 1 (FARP1), which is a guanine nucleotide exchange factor (GEF) of the RhoGTPases RAC1 and RhoA. ANKK1–FARP1 colocalized in F-ACTIN-rich structures for neuronal maturation and migration, and both proteins activate the Wnt/PCP pathway. ANKK1, but not FARP1, promotes neuritogenesis, and both proteins are involved in neuritic spine outgrowth. Notably, the knockdown of ANKK1 or FARP1 affects RhoGTPases expression and neural differentiation. Additionally, ANKK1 binds WGEF, another GEF of Wnt/PCP, regulating its interaction with RhoA. During neuronal differentiation, ANKK1–WGEF interaction is downregulated, while ANKK1–FARP1 interaction is increased, suggesting that ANKK1 recruits Wnt/PCP components for bidirectional control of F-ACTIN assembly. Our results suggest a brain structural basis in TaqIA-associated phenotypes. Full article

Background: Major depressive disorder (MDD) is a disease that has been increasingly affecting more people worldwide. The dopamine D2 receptor (DRD2), encoded by the DRD2 gene, plays critical roles in the brain, one of which is related to reward processes. Aims: The following systematic review aims to analyze the DRD2/ANKK1 TaqIA (rs1800497) polymorphism’s A1 genotype frequency fluctuation in MDD patients and determine its influence on MDD. Methods: Four databases were searched, and the consequent articles were analyzed following the inclusion criteria per the PECOS strategy, resulting in five selected articles. Results: Interestingly, although two articles showed that the A1 allele presence significantly increases the risk of MDD manifestation, most articles did not find a significant association between this DRD2 gene variant and MDD. Conclusions: Most of the included studies were dated, indicating the need for more studies to address the results’ non-conformity with different populations. Full article

Pulmonary fibrosis (PF) is a severe, irreversible lung disease characterized by progressive scarring, with idiopathic pulmonary fibrosis (IPF) being the most prevalent form. IPF’s pathogenesis involves repetitive lung epithelial injury leading to fibroblast activation and excessive extracellular matrix (ECM) deposition. The prognosis for IPF is poor, with limited therapeutic options like nintedanib and pirfenidone offering only modest benefits. Emerging research highlights the dysregulation of the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling pathway as a critical factor in PF. YAP and TAZ, components of the Hippo pathway, play significant roles in cell proliferation, differentiation, and fibrosis by modulating gene expression through interactions with TEA domain (TEAD) transcription factors. The aberrant activation of YAP/TAZ in lung tissue promotes fibroblast activation and ECM accumulation. Targeting the YAP/TAZ pathway offers a promising therapeutic avenue. Preclinical studies have identified potential treatments, such as trigonelline, dopamine receptor D1 (DRD1) agonists, and statins, which inhibit YAP/TAZ activity and demonstrate antifibrotic effects. These findings underscore the importance of YAP/TAZ in PF pathogenesis and the potential of novel therapies aimed at this pathway, suggesting a new direction for improving IPF treatment outcomes. Further research is needed to validate these approaches and translate them into clinical practice. Full article

Background: Alexithymia is a trait involving difficulties in processing emotions. Genetic association studies have investigated candidate genes involved in alexithymia’s pathogenesis. Therefore, the aim of the present study was to perform a systematic review of the genetic background associated with alexithymia. Methods: A systematic review of genetic studies of people with alexithymia was conducted. Electronic databases including PubMed, Scopus, and Web of Science were searched for the study purpose. We used the words “Alexithymia”, “gene”, “genetics”, “variants”, and “biomarkers”. The present systematic review was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. We found only candidate gene studies. A total of seventeen studies met the eligibility criteria, which comprised 22,361 individuals. The candidate genes associated with alexithymia were the serotoninergic pathway genes solute carrier family 6 member 4 (SLC6A4), serotonin 1A receptor (HTR1A), and serotonin 1A receptor (HTR2A); the neurotransmitter metabolism genes dopamine receptor D2 (DRD2), ankyrin repeat and kinase domain containing 1 (ANKK1), catechol-o-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and oxytocin receptor (OXTR); and other pathway genes, vitamin D-binding protein (VDBP), tumor protein P53 regulated apoptosis inducing protein 1 (TP53AIP1), Rho GTPase Activating Protein 32 (ARHGAP32), and transmembrane protein 88B (TMEM88B). Conclusion: The results of this study showed that only case–control gene studies have been performed in alexithymia. On the basis of our findings, the majority of alexithymia genes and polymorphisms in this study belong to the serotoninergic pathway and neurotransmitter metabolism genes. These data suggest a role of serotoninergic neurotransmission in alexithymia. Nevertheless, more and future research is required to learn about the role of these genes in alexithymia. Full article

Currently, there is a growing amount of evidence for the involvement of dopamine receptors and the functionally related trace amine-associated receptor, TAAR1, in upper intestinal function. In the present study, we analyzed their expression in the duodenum using publicly accessible transcriptomic data. We revealed the expression of DRD1, DRD2, DRD4, DRD5, and TAAR1 genes in different available datasets. The results of the gene ontology (GO) enrichment analysis for DRD2 and especially TAAR1 co-expressed genes were consistent with the previously described localization of D2 and TAAR1 in enteric neurons and secretory cells, respectively. Considering that co-expressed genes are more likely to be involved in the same biological processes, we analyzed genes that are co-expressed with TAAR1, DRD2, DRD4, and DRD5 genes in healthy mucosa and duodenal samples from patients with functional dyspepsia (FD) or diabetes-associated gastrointestinal symptoms. Both pathological conditions showed a deregulation of co-expression patterns, with a high discrepancy between DRDs and TAAR1 co-expressed gene sets in normal tissues and patients’ samples and a loss of these genes’ functional similarity. Meanwhile, we discovered specific changes in co-expression patterns that may suggest the involvement of TAAR1 and D5 receptors in pathologic or compensatory processes in FD or diabetes accordingly. Despite our findings suggesting the possible role of TAAR1 and dopamine receptors in functional diseases of the upper intestine, underlying mechanisms need experimental exploration and validation. Full article

Traumatic brain injury (TBI) is associated with an increased risk of developing Parkinson’s disease (PD), though the exact mechanisms remain unclear. TBI triggers acute neuroinflammation and catecholamine dysfunction post-injury, both implicated in PD pathophysiology. The long-term impact on these pathways following TBI, however, remains uncertain. In this study, male Sprague-Dawley rats underwent sham surgery or Marmarou’s impact acceleration model to induce varying TBI severities: single mild TBI (mTBI), repetitive mild TBI (rmTBI), or moderate–severe TBI (msTBI). At 12 months post-injury, astrocyte reactivity (GFAP) and microglial levels (IBA1) were assessed in the striatum (STR), substantia nigra (SN), and prefrontal cortex (PFC) using immunohistochemistry. Key enzymes and receptors involved in catecholaminergic transmission were measured via Western blot within the same regions. Minimal changes in these markers were observed, regardless of initial injury severity. Following mTBI, elevated protein levels of dopamine D1 receptors (DRD1) were noted in the PFC, while msTBI resulted in increased alpha-2A adrenoceptors (ADRA2A) in the STR and decreased dopamine beta-hydroxylase (DβH) in the SN. Neuroinflammatory changes were subtle, with a reduced number of GFAP+ cells in the SN following msTBI. However, considering the potential for neurodegenerative outcomes to manifest decades after injury, longer post-injury intervals may be necessary to observe PD-relevant alterations within these systems. Full article