RESUMEN

Psychosis is a characterizing feature of many mental disorders that dramatically affects human thoughts and perceptions, influencing the ability to distinguish between what is real and what is not. Both genetic and environmental factors, such as stressful events or drug use, play a pivotal role in the development of symptomatology and therefore changes in the epigenome may be of relevance in modeling a psychotic phenotype. According to the well-documented dysregulation of endocannabinoid and dopaminergic system genes in schizophrenia, we investigated DNA methylation cannabinoid type 1 receptor (CNR1) and dopamine D2 receptor (DRD2) genes in saliva samples from psychotic subjects using pyrosequencing. The epigenetic mark was significantly higher and directly correlated for both genes in psychotic subjects compared to healthy controls. We also showed that these DNA methylation levels were lower in psychotic subjects reporting current delta-9-tetrahydrocannabinol (THC) consumption, a well-known risk factor for developing psychosis throughout the lifespan, resembling those of controls at least for the DRD2 gene. Overall, our data confirm the key role of CNR1 and DRD2 gene regulation in psychosis and suggest DNA methylation levels at specific CpG sites as potential biomarkers, but just in those psychotic subjects not consuming THC.

RESUMEN

The dopamine D2 receptor (DRD2) represents a pivotal target for therapeutic intervention in the treatment of neuropsychiatric disorders, including schizophrenia, bipolar disorder, and Parkinson's disease. The successful discovery of numerous effective DRD2 inhibitors has led to their clinical application and ongoing evaluation in various clinical trials. This review explores the synthetic approaches and clinical applications of prototypical small-molecule DRD2 inhibitors that have received approval or are currently undergoing clinical trials, highlighting their therapeutic potential and challenges. The synthesis of these inhibitors employs various chemical strategies, including modifications of phenothiazine and butyrophenone structures, which have yielded significant antipsychotic agents like chlorpromazine and haloperidol. Additionally, newer classes of inhibitors, such as aripiprazole, exhibit partial agonist activity at DRD2, offering a unique therapeutic profile. Clinically, DRD2 inhibitors demonstrate efficacy in managing positive symptoms of schizophrenia, manic episodes in bipolar disorder, and dopaminergic imbalance in Parkinson's disease. However, the emergence of adverse effects, including tardive dyskinesia, extrapyramidal symptoms and metabolic syndrome, presents substantial challenges. Advances in the development of second-generation antipsychotics aim to balance efficacy with a better side effect profile by targeting additional neurotransmitter receptors. This review aims to deliver an overview of the synthesis and clinical applications of representative small-molecule DRD2 inhibitors across various clinical phases, thereby offering strategic insights for the advancement of DRD2 inhibitor development.

Asunto(s)

Antipsicóticos , Antagonistas de los Receptores de Dopamina D2 , Receptores de Dopamina D2 , Animales , Humanos , Antipsicóticos/farmacología , Antipsicóticos/síntesis química , Antipsicóticos/química , Antagonistas de los Receptores de Dopamina D2/farmacología , Antagonistas de los Receptores de Dopamina D2/síntesis química , Antagonistas de los Receptores de Dopamina D2/química , Estructura Molecular , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Relación Estructura-Actividad

RESUMEN

Different dopamine (DA) subtypes have opposing dynamics at postsynaptic receptors, with the ratio of D1 to D2 receptors determining the relative sensitivity to gains and losses, respectively, during value-based learning. This effective sensitivity to different reward feedback interacts with phasic DA levels to determine the effectiveness of learning, particularly in dynamic feedback situations where the frequency and magnitude of rewards need to be integrated over time to make optimal decisions. We modeled this effect in simulations of the underlying basal ganglia pathways and then tested the predictions in individuals with a variant of the human dopamine receptor D2 (DRD2; -141C Ins/Del and Del/Del) gene that associates with lower levels of D2 receptor expression (N = 119) and compared their performance in the Iowa Gambling Task to noncarrier controls (N = 319). Ventral striatal (VS) reactivity to rewards was measured in the Cards task with fMRI. DRD2 variant carriers made less effective decisions than noncarriers, but this effect was not moderated by VS reward reactivity as is hypothesized by our model. These results suggest that the interaction between DA receptor subtypes and reactivity to rewards during learning may be more complex than originally thought.

Asunto(s)

Toma de Decisiones , Imagen por Resonancia Magnética , Receptores de Dopamina D2 , Refuerzo en Psicología , Recompensa , Humanos , Receptores de Dopamina D2/metabolismo , Toma de Decisiones/fisiología , Masculino , Femenino , Adulto , Adulto Joven , Imagen por Resonancia Magnética/métodos

RESUMEN

Several studies are published, that investigated dopamine receptor 2 (DRD2) gene TaqIA polymorphism as a risk factor for alcohol dependence (AD) with positive and negative associations. To derive a more precise estimation of the relationship, a meta-analysis of case-control studies that examined the association between DRD2 gene Taq1A polymorphism and alcohol dependence was performed. Eligible articles were identified through a search of databases including PubMed, Science Direct, Springer link, and Google Scholar. The association between the DRD2 TaqIA polymorphism and AD susceptibility was conducted using odds ratios (ORs) and 95% confidence intervals (95% CIs) as association measures. A total of 69 studies with 9125 cases and 9123 healthy controls were included in the current meta-analysis. Results of the present analysis showed significant association between DRD2 TaqIA polymorphism and AD risk using five genetic modes (allele contrast model-OR 1.22, 95% CI 1.13-1.32, p < 0.0001; homozygote model-OR 1.35, 95%CI 1.18-1.55; p ≤ 0.0001; dominant model-OR 1.29; 95% CI 1.20-1.39; p < 0.0001; recessive model-OR 1.21; 95% CI 1.08-1.36; p = 0.0006). There was no significant association found in subgroup analysis, TaqIA polymorphism was not significantly associated with AD risk in the Asian population under all genetic models, but in the Caucasian population, TaqIA polymorphism was significantly associated with AD risk. Overall, results support the hypothesis that DRD2 Taq1A polymorphism plays a role in alcohol dependence.

RESUMEN

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.

RESUMEN

Peers are important socializers of adolescent prosocial behavior. Still, the proximal cognitive and emotional process underlying this link and the sources of individual differences in sensitivity to peer influence have yet to be explored. Utilizing the gene-gene-environment (G × G × E) approach and multi-informant measurement, this study investigated how peer relationships operate to influence adolescent prosocial behavior by examining the mediating role of cognitive and emotional empathy, and the moderating role of the OXTR and DRD2 genes. The study utilized longitudinal data from a community sample of Chinese adolescents (N = 1080, Mage = 13.32 years at T1). Results showed that cognitive empathy rather than emotional empathy mediated the link between peer acceptance/rejection and prosocial behavior. Furthermore, the association among peer acceptance, cognitive empathy, and prosocial behavior was moderated by OXTR and DRD2. Specifically, adolescents with the combinations of AA/AA or G/G genotypes of OXTR/DRD2 benefited more from peer acceptance compared to their counterparts carrying other combined genotypes. The findings highlight cognitive empathy as a proximal process linking peer interaction to prosocial behavior and lend support to the interaction between oxytocinergic and dopaminergic systems on environmental sensitivity.

RESUMEN

The maturation of forebrain dopamine circuitry occurs over multiple developmental periods, extending from early postnatal life until adulthood, with the precise timing of maturation defined by the target region. We recently demonstrated in the adult mouse brain that axon terminals arising from midbrain dopamine neurons innervate the anterior corpus callosum and that oligodendrocyte lineage cells in this white matter tract express dopamine receptor transcripts. Whether corpus callosal dopamine circuitry undergoes maturational changes between early adolescence and adulthood is unknown but may be relevant to understanding the dramatic micro- and macro-anatomical changes that occur in the corpus callosum of multiple species during early adolescence, including in the degree of myelination. Using quantitative neuroanatomy, we show that dopamine innervation in the forceps minor, but not the rostral genu, of the corpus callosum, is greater during early adolescence (P21) compared to adulthood (>P90) in wild-type mice. We further demonstrate with RNAscope that, as in the adult, Drd1 and Drd2 transcripts are expressed at higher levels in oligodendrocyte precursor cells (OPCs) and decline as these cells differentiate into oligodendrocytes. In addition, the number of OPCs that express Drd1 transcripts during early adolescence is double the number of those expressing the transcript during early adulthood. These data further implicate dopamine in axon myelination and myelin regulation. Moreover, because developmental (activity-independent) myelination peaks during early adolescence, with experience-dependent (activity-dependent) myelination greatest during early adulthood, our data suggest that potential roles of dopamine on callosal myelination shift between early adolescence and adulthood, from a developmental role to an experience-dependent role.

Asunto(s)

Cuerpo Calloso , Ratones Endogámicos C57BL , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Animales , Ratones , Cuerpo Calloso/metabolismo , Cuerpo Calloso/crecimiento & desarrollo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Masculino , Neuronas Dopaminérgicas/metabolismo , Dopamina/metabolismo , Células Precursoras de Oligodendrocitos/metabolismo , Femenino

RESUMEN

Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRN→arcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.

RESUMEN

Schizophrenia is a serious mental illness with unknown etiology, and shows increasing incidence and high lifetime prevalence rate. The main receptors related to the disease are DRD2 and 5-HTR2A. Thus, a comprehensive understanding of the interaction mode between antipsychotic drugs with relevant receptors is very important for developing more effective drugs. 5-HTR2A-SNAP-Tag/CMC and DRD2-SNAP-Tag/CMC models constructed in this work provided a new method for studying the interaction between atypical antipsychotics and the two receptors. The results of comparative experiments showed that the new models not only met the high selectivity and specificity of the screening requirements but were also more stable and long-lasting than the traditional CMC model. Binding assays showed that the effects of three atypical antipsychotics (including clozapine, olanzapine, and quetiapine) on 5-HTR2A were stronger than their effects on DRD2. Additionally, two potentially active components, magnolol and honokiol, were screened in Magnolia officinalis methanol extract using the 5-HTR2A-SNAP-Tag/CMCHPLC-MS system. Nonlinear chromatographic analysis and molecular docking were conducted to study the interactions between screened compounds and the two receptors. The binding constants (KA) of magnolol and honokiol with 5-HTR2A were 17,854 ± 1,117 M-1 and 38,858 ± 4,964 M-1, respectively, and KA values with DRD2 were 4,872 ± 1,618 M-1 and 20,692 ± 10,267 M-1, respectively. We concluded that the established models are reliable for studying receptor-ligand interactions and screening antagonists of schizophrenia.

Asunto(s)

Compuestos Alílicos , Antipsicóticos , Compuestos de Bifenilo , Lignanos , Magnolia , Fenoles , Esquizofrenia , Antipsicóticos/farmacología , Antipsicóticos/química , Magnolia/química , Ligandos , Simulación del Acoplamiento Molecular , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo

RESUMEN

Objective: The study aimed to explore the genotype and allele distributions of dopamine D2-like receptor (DRD2) gene -141C and C957T polymorphisms in the Chinese Han population with dyslipidemia, as well as their association with serum lipid levels. Methods: One hundred fifty patients with dyslipidemia and 150 healthy people were recruited as the case and the control groups, respectively. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol levels were detected. The target sequence of DRD2 polymorphisms was amplified by polymerase chain reaction and genotyped via Sanger sequencing. Results: In DRD2 gene C957T (rs6277), three genotypes of CC, CT, and TT were detected with the frequencies of 92.67%, 6.67%, 0.67% in dyslipidemia cases, and 83.33%, 14.67%, 2.00% in the controls, respectively. The CT genotype and T allele frequencies were significantly low in the case group relative to the control group. After adjusting to other clinical indicators, the CT genotype of C957T polymorphism (hazard ratio = 0.401, 95% confidence interval = 0.181-0.890, p < 0.05) was still related to a significantly reduced risk of dyslipidemia. The C957T CT genotype carriers had the lowest values of serum TC, TG, LDL, and the highest values of serum HDL-C. Conclusion: DRD2 gene C957T polymorphism was an independent influencing factor associated with the susceptibility to dyslipidemia, and the CT genotype was associated with decreased odds of susceptibility to dyslipidemia.

RESUMEN

BACKGROUND: Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported. METHODS: Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR). RESULTS: Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness. CONCLUSIONS: H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location.

Asunto(s)

Neoplasias Encefálicas , Glioma , Imidazoles , Mutación , Recurrencia Local de Neoplasia , Receptores de Dopamina D2 , Humanos , Glioma/genética , Glioma/tratamiento farmacológico , Glioma/patología , Masculino , Femenino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Receptores de Dopamina D2/genética , Adulto , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Antagonistas de los Receptores de Dopamina D2/uso terapéutico , Antagonistas de los Receptores de Dopamina D2/farmacología , Pirimidinas/uso terapéutico , Pronóstico , Adulto Joven , Estudios de Seguimiento , Estudios de Cohortes , Agonistas de Dopamina/uso terapéutico , Piridinas/uso terapéutico , Piridinas/farmacología

RESUMEN

Attention-deficit hyperactivity disorder is a highly inherited neurodevelopmental disorder. Previous genetic research has linked ADHD to certain genes in the dopaminergic synaptic pathway. Nonetheless, research on this relationship has produced varying results across various populations. China is a multi-ethnic country with its own unique genetic characteristics. Therefore, such a population can provide useful information about the relationship between gene polymorphisms in dopaminergic synaptic pathways and ADHD. This study looked at the genetic profiles of 284 children in China's Xinjiang. In total, 142 ADHD children and 142 control subjects were enrolled. Following the extraction of DNA from oral mucosal cells, 13 SNPs for three candidate genes (SLC6A3, DRD2, and GRIN2B) in the dopaminergic synaptic pathway of ADHD were screened. Based on the results of single nucleotide polymorphism (SNP) analyses, we found that the DRD2 gene variants rs6277 and rs6275, and the SLC6A3 gene variant rs2652511, were significantly associated with ADHD in boys and girls, respectively, after adjusting for false discovery rate (FDR) in terms of allele frequencies. Furthermore, our generalized multifactorial downscaling approach identified a significant association between rs6275 and rs1012586. These findings suggest that DRD2 and SLC6A3 genes have a crucial role in ADHD susceptibility. Additionally, we observed that the interaction between GRIN2B and DRD2 genes may contribute to the susceptibility of Chinese children with ADHD.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Receptores de Dopamina D2 , Receptores de N-Metil-D-Aspartato , Niño , Femenino , Humanos , Masculino , Trastorno por Déficit de Atención con Hiperactividad/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Receptores de Dopamina D2/genética , Receptores de N-Metil-D-Aspartato/genética

RESUMEN

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with extraordinarily limited treatment options and uniformly fatal prognosis. Histone H3K27M mutation is a common recurrent alteration in DIPG and disrupts epigenetic regulation. We hypothesize that genome-wide H3K27M-induced epigenetic dysregulation makes tumors vulnerable to epigenetic targeting. METHODS: We performed a screen of compounds targeting epigenetic enzymes to identify potential inhibitors for the growth of patient-derived DIPG cells. We further carried out transcriptomic and genomic landscape profiling including RNA-seq and CUT&RUN-seq as well as shRNA-mediated knockdown to assess the effects of chaetocin and SUV39H1, a target of chaetocin, on DIPG growth. RESULTS: High-throughput small-molecule screening identified an epigenetic compound chaetocin as a potent blocker of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis of DIPG cells and significantly extended survival in DIPG xenograft models, while restoring H3K27me3 levels. Moreover, the loss of H3K9 methyltransferase SUV39H1 inhibited DIPG cell growth. Transcriptomic and epigenomic profiling indicated that SUV39H1 loss or inhibition led to the downregulation of stemness and oncogenic networks including growth factor receptor signaling and stemness-related programs; however, D2 dopamine receptor (DRD2) signaling adaptively underwent compensatory upregulation conferring resistance. Consistently, a combination of chaetocin treatment with a DRD2 antagonist ONC201 synergistically increased the antitumor efficacy. CONCLUSIONS: Our studies reveal a therapeutic vulnerability of DIPG cells through targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops for treating this devastating disease. Combining SUV39H1-targeting chaetocin with other agents such as ONC201 may offer a new strategy for effective DIPG treatment.

Asunto(s)

Neoplasias del Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Imidazoles , Piridinas , Pirimidinas , Niño , Humanos , Epigénesis Genética , Histonas/genética , Glioma Pontino Intrínseco Difuso/genética , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Neoplasias del Tronco Encefálico/genética , Neoplasias del Tronco Encefálico/patología , Metiltransferasas/genética , Metiltransferasas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Piperazinas

RESUMEN

BACKGROUND: Dopamine receptor D2 (DRD2) TaqIA polymorphism has an influence on addiction treatment response and prognosis by mediating brain dopaminergic system efficacy. Insula is crucial for conscious urges to take drugs and maintain drug use. However, it remains unclear about the contribution of DRD2 TaqIA polymorphism to the regulation of insular on addiction behavioral and its relation with the therapeutic effect of methadone maintenance treatment (MMT). METHODS: 57 male former heroin dependents receiving stable MMT and 49 matched male healthy controls (HC) were enrolled. Salivary genotyping for DRD2 TaqA1 and A2 alleles, brain resting-state functional MRI scan and a 24-month follow-up for collecting illegal-drug-use information was conducted and followed by clustering of functional connectivity (FC) patterns of HC insula, insula subregion parcellation of MMT patients, comparing the whole brain FC maps between the A1 carriers and non-carriers and analyzing the correlation between the genotype-related FC of insula sub-regions with the retention time in MMT patients by Cox regression. RESULTS: Two insula subregions were identified: the anterior insula (AI) and the posterior insula (PI) subregion. The A1 carriers had a reduced FC between the left AI and the right dorsolateral prefrontal cortex (dlPFC) relative to no carriers. And this reduced FC was a poor prognostic factor for the retention time in MMT patients. CONCLUSION: DRD2 TaqIA polymorphism affects the retention time in heroin-dependent individuals under MMT by mediating the functional connectivity strength between left AI and right dlPFC, and the two brain regions are promising therapeutic targets for individualized treatment.

Asunto(s)

Dependencia de Heroína , Heroína , Humanos , Masculino , Heroína/uso terapéutico , Corteza Prefontal Dorsolateral , Polimorfismo Genético/genética , Dependencia de Heroína/diagnóstico por imagen , Dependencia de Heroína/tratamiento farmacológico , Dependencia de Heroína/genética , Metadona/uso terapéutico , Imagen por Resonancia Magnética , Receptores de Dopamina D2/genética

RESUMEN

Drugs acting on dopamine D2 receptors are widely used for the treatment of several neuropsychiatric disorders, including schizophrenia and depression. Social deficits are a core symptom of these disorders. Pharmacological manipulation of dopamine D2 receptors (Drd2), a Gi-coupled subtype of dopamine receptors, in the medial prefrontal cortex (mPFC) has shown that Drd2 is implicated in social behaviors. However, the type of neurons expressing Drd2 in the mPFC and the underlying circuit mechanism regulating social behaviors remain largely unknown. Here, we show that Drd2 were mainly expressed in pyramidal neurons in the mPFC and that the activation of the Gi-pathway in Drd2+ pyramidal neurons impaired social behavior in male mice. In contrast, the knockdown of D2R in pyramidal neurons in the mPFC enhanced social approach behaviors in male mice and selectively facilitated the activation of mPFC neurons projecting to the nucleus accumbens (NAc) during social interaction. Remarkably, optogenetic activation of mPFC-to-NAc-projecting neurons mimicked the effects of conditional D2R knockdown on social behaviors. Altogether, these results demonstrate a cell type-specific role for Drd2 in the mPFC in regulating social behavior, which may be mediated by the mPFC-to-NAc pathway.

Asunto(s)

Células Piramidales , Receptores de Dopamina D2 , Ratones , Masculino , Animales , Receptores de Dopamina D2/metabolismo , Células Piramidales/fisiología , Neuronas/metabolismo , Corteza Prefrontal/metabolismo , Núcleo Accumbens/fisiología , Conducta Social

RESUMEN

The medial preoptic area (mPOA) regulates the probability and intensity of singing behavior in birds. Polzin and colleagues examined the molecular changes in the mPOA that were associated with gregarious song in European starlings (Sturnus vulgaris). High-throughput transcriptome analyses identified glutamate and dopamine pathways were highly enriched with gregarious song.

Asunto(s)

Estorninos , Vocalización Animal , Animales , Vocalización Animal/fisiología , Conducta Sexual Animal/fisiología , Conducta Social , Estorninos/metabolismo , Dopamina/metabolismo , Área Preóptica/metabolismo

Asunto(s)

Adicción a la Comida , Humanos , Marcadores Genéticos , Receptores de Dopamina D2/genética

RESUMEN

BACKGROUND: Post-traumatic stress disorder (PTSD) is a trauma- or stressor-related mental health condition with high socioeconomic burden. We aimed in this review to identify promising genetic markers predisposing for PTSD, which might serve in the design subsequent studies aiming to develop PTSD prevention and remediation measures. SUBJECTS AND METHODS: Our search queries in the PubMed database yielded 547 articles, of which 20 met our inclusion criteria for further analysis: published between 2018 and 2022, original research, containing molecular-genetic and statistical data, containing diagnosis verification methods, PTSD as a primary condition, and a sample of at least 60 patients. RESULTS: Among the 20 analyzed studies were reports of significant associations between PTSD and: FKBP5 variants rs9470080, regardless of the C or T allele; two FKBP5 haplotypes (A-G-C-C and A-G-C-T); gene-gene DRDхANNK1-COMT (rs1800497 × rs6269) and OXTR-DRD2 (rs2268498 × rs1801028); C-allele of CRHR1 (rs1724402). Other findings, such as the association of FKBP5 haplotypes (A-G-C-C, A-G-C-T) and the FKBP5-CRHR1 genotype, were of lesser statistical significance and less extensively studied. CONCLUSIONS: Although our literature analysis implicates certain genetic factors in PTSD, our understanding of the polygenic nature underlying the disorder remains limited, especially considering the hitherto underexplored epigenetic mechanisms. Future research endeavors should prioritize exploring these aspects to provide a more nuanced understanding of PTSD and its genetic underpinnings.

Asunto(s)

Trastornos por Estrés Postraumático , Humanos , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/prevención & control , Trastornos por Estrés Postraumático/diagnóstico , Haplotipos , Polimorfismo de Nucleótido Simple , Genotipo , Alelos

RESUMEN

Since 1990, there have been thousands of published studies on addiction psychiatry. Several from Blum et al showed the clinical relevance of the Genetic Addiction Risk Severity (GARS) test in identifying risk for reward deficiency behaviors in cohorts from polysubstance abuse and pain clinics, post-surgical bariatrics, and DWI offenders facing prison time. Since Blum et al first published in JAMA (1990) concerning the association of the DRD2 gene polymorphism and severe alcoholism, reactions have been mixed. More recently, however, a meta-analysis of 62 studies showed a significant association between DRD2 rs1800497 and Alcohol Use Disorder (AUD). Other studies from Yale University showed that a haplotype block of the DRD2 gene A1 allele was associated with AUD and heroin dependence. GWAS studies of depression and suicide in 1.2 million veterans confirmed the first psychiatric candidate gene study finding from Blum et al 1990; a significant association between the minor DRD2 allele, Taq A1 and severe alcoholism. Additionally, the DRD2 rs1800497 is robustly associated with suicidal behaviors. Furthermore, DNA polymorphic alleles underlying substance use disorder (SUD) with multiple substances were mapped via chromatin refolding, revealing that the DRD2 gene and associated polymorphism(s) as the top gene signal. Based on these investigations, we conclude that GWAS should end the controversy about the DRD2 gene being one determinant of Reward Deficiency Syndrome (RDS) first reported in 1996.

RESUMEN

Motor dysfunction in Parkinson's disease (PD) is closely linked to the dopaminergic depletion of striatal neurons and altered synaptic plasticity at corticostriatal synapses. Dopamine receptor D1 (DRD1) stimulation is a crucial step in the formation of long-term potentiation (LTP), whereas dopamine receptor D2 (DRD2) stimulation is needed for the formation of long-term depression (LTD) in striatal spiny projection neurons (SPNs). Tropomyosin receptor kinase B (TrkB) and its ligand brain-derived neurotrophic factor (BDNF) are centrally involved in plasticity regulation at the corticostriatal synapses. DRD1 activation enhances TrkB's sensitivity for BDNF in direct pathway spiny projection neurons (dSPNs). In this study, we showed that the activation of DRD2 in cultured striatal indirect pathway spiny projection neurons (iSPNs) and cholinergic interneurons causes the retraction of TrkB from the plasma membrane. This provides an explanation for the opposing synaptic plasticity changes observed upon DRD1 or DRD2 stimulation. In addition, TrkB was found within intracellular structures in dSPNs and iSPNs from Pitx3-/- mice, a genetic model of PD with early onset dopaminergic depletion in the dorsolateral striatum (DLS). This dysregulated BDNF/TrkB signaling might contribute to the pathophysiology of direct and indirect pathway striatal projection neurons in PD.