Functionally Antagonistic Transcription Factors IRF1 and IRF2 Regulate the Transcription of the Dopamine Receptor D2 Gene Associated with Aggressive Behavior of Weaned Pigs

Aggressive behavior has negative effects on animal welfare and growth performance in pigs. The dopamine receptor D2 (DRD2) has a critical neuromodulator role in the dopamine signal pathway within the brain to control behavior. A functional single-nucleotide polymorphism (SNP), rs1110730503, in the promoter region of the porcine DRD2 gene was identified, which affects aggressive behavior in pigs. A chromatin immunoprecipitation (ChIP) assay was used to identify the interactions between interferon regulatory factor 1 (IRF1) and IRF2 with the DRD2 gene. The overexpression or knockdown of these two transcription factors in porcine kidney-15 (PK15) and porcine neuronal cells (PNCs) indicate that the binding of IRF1 to DRD2 promotes the transcription of the DRD2 gene, but the binding of IRF2 to the DRD2 gene inhibits its transcription. Furthermore, IRF1 and IRF2 are functionally antagonistic to each other. The downregulation of DRD2 or upregulation of IRF2 increased the apoptosis rate of porcine neuroglial cells. Taken together, we found that transcriptional factors IRF1 and IRF2 have vital roles in regulating the transcription of the DRD2 gene, and rs1110730503 (−915A/T) is a functional SNP that influences IRF2 binding to the promoter of the DRD2 gene. These findings will provide further insight towards controlling aggressive behavior in pigs.

Initial Study on COMT and DRD2 Gene Polymorphisms as Well as the Influence of Temperament and Character Trait on the Severity of Alcohol Craving in Alcohol-Dependent Patients

The main aim of this work was to determine the impact of COMT and DRD2 gene polymorphisms together with temperament and character traits on alcohol craving severity alcohol-dependent persons. The sample comprised of 89 men and 16 women (aged 38±7). For the sake of psychological assessment various analytic methods have been applied like the Short Alcohol Dependence Data Questionnaire (SADD), Penn Alcohol Craving Scale (PACS) or Temperament and Character Inventory (TCI) test. The SNP polymorphism of the analyzed genes was determined by Real Time PCR test. The results showed, that the COMT polymorphismmay have an indirected relationship with the intensity and changes in alcohol craving during abstinence. The DRD2 receptor gene polymorphisms are related with the intensity of alcohol craving. It seems that the character traits like “self-targeting”, including “self-acceptance”, are more closely related to the severity of alcohol craving and polymorphic changes in the DRD2 receptor than temperamental traits. Although this is a pilot study the obtained results appeared to be promising and clearly indicate the link betweengene polymorphisms alcohol craving and its severity.

Paternal Aggression in Early-Life Impairs the Spatial Memory and Passive Avoidance Learning in Adulthood of Male Rats: The Possible Role of DRD2

Negative early-life experiences (e.g., having an aggressive father) can leave long-lasting impacts on the behavior. However, it is not clear if they influence learning and memory. In this study, we investigated the influences that the presence of an aggressive father had on the level of passive avoidance learning and spatial memory. We also studied the changes in the dopamine receptor D2 (DRD2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) gene expression in the hippocampus. Then, we evaluated if a DRD2 antagonist (Sulpiride, 0.125, 0.25, or 0.5 µg/rat) could modulate these changes. We found that the subjects exposed to early-life stress made by aggressive fathers had impaired passive avoidance learning and spatial memory than those with normal fathers. Treatment with Sulpiride improved passive avoidance learning and spatial memory in rats with aggressive fathers. The rats with aggressive fathers also had higher expression of the DRD2 gene in their hippocampus than those with normal fathers, while the PGC-1α gene expression was not different among groups. Treatment with Sulpiride (0.125, 0.25, or 0.5 µg/rat) reduced the DRD2 gene expression in those with aggressive fathers to the normal level in those with normal fathers. These data suggest that living in a shared place with an aggressive father, even without any physical contact, can detrimentally affect passive avoidance learning and spatial memory which is accompanied by the increased expression of the DRD2 gene. Also, Sulpiride as a dopaminergic antagonist could reverse this process.

A comprehensive in silico investigation into the nsSNPs of Drd2 gene predicts significant functional consequences in dopamine signaling and pharmacotherapy

DRD2 is a neuronal cell surface protein involved in brain development and function. Variations in the Drd2 gene have clinical significance since DRD2 is a pharmacotherapeutic target for treating psychiatric disorders like ADHD and schizophrenia. Despite numerous studies on the disease association of single nucleotide polymorphisms (SNPs) in the intronic regions, investigation into the coding regions is surprisingly limited. In this study, we aimed at identifying potential functionally and pharmaco-therapeutically deleterious non-synonymous SNPs of Drd2. A wide array of bioinformatics tools was used to evaluate the impact of nsSNPs on protein structure and functionality. Out of 260 nsSNPs retrieved from the dbSNP database, initially 9 were predicted as deleterious by 15 tools. Upon further assessment of their domain association, conservation profile, homology models and inter-atomic interaction, the mutant F389V was considered as the most impactful. In-depth analysis of F389V through Molecular Docking and Dynamics Simulation revealed a decline in affinity for its native agonist dopamine and an increase in affinity for the antipsychotic drug risperidone. Remarkable alterations in binding interactions and stability of the protein-ligand complex in simulated physiological conditions were also noted. These findings will improve our understanding of the consequence of nsSNPs in disease-susceptibility and therapeutic efficacy.

Dopamine Receptor D2 Gene (DRD2) Polymorphisms, Job Stress, and Their Interaction on Sleep Dysfunction

Recent studies have shown that incessant job stress could eventually result in sleep dysfunction (SD), and most importantly, the essential role dopamine receptor D2 (DRD2) gene polymorphisms play in the psychopathological mechanism of SD. The Effort-Reward Imbalance scale and the Pittsburgh Sleep Quality Index were both used to access SD and job stress (JS). A significant negative correlation was observed between the sDA levels and SD subscale scores (sleep efficiency, daytime dysfunction). The findings revealed that high levels of JS were linked to a higher SD score (OR = 2.13, 95% CI: 1.46–3.12). Likewise, the homozygous A1A1 genotype of DRD2 rs1800497 was more likely to be associated with SD (OR = 2.90, 95% CI: 1.75–4.82). Compared to participants with low JS and heterozygous A1A2/A2A2 genotype, those with both high JS and homozygous A1A1 genotype had a higher SD score (OR = 5.40, 95% CI: 2.89–10.11). The A1 allele of the DRD2 rs1800497 polymorphism also enhances the likelihood of SD when undergoing JS. Besides, subjects with low JS and the homozygous A1A1 genotype also showed an increased possibility for sleep dysfunction (OR = 2.05, 95% CI: 1.03–4.11). Our results suggest that the DA system may interrelate with JS to affect sleep.

Gen DRD2, TH y DTNBP1 y la sintomatología de pacientes ecuatorianos esquizofrénicos tratados con haloperidol. Caso Clínico.

Genetic variants of chemical neurotransmission have been associated with the development of schizophrenia. This is a syndromic mental disorder that affects the perception of reality and feelings of those affected. This disease is expressed in 1% of the world’s population; in all cases, antipsychotic drugs are used as treatment. Scientific evidence indicates that symptomatologic characteristics and therapeutic response has a genetic influence. The objective of the current work was to describe the presence or absence of allelic polymorphisms found on the dopamine gene and the therapeutic response of 11 Ecuadorian individuals treated with haloperidol (5mg.), for a period of 14 days. Single Nucleotide Polymorphisms (SNPs) in the DRD2, TH and DTNBP1 genes and evaluations recorded from the PANSS, BPRS and UKU scales were assessed. An association with a significance of P = 0.024 was found between the Taq1-B polymorphism on the DRD2 gene and the BPRS positive symptom scale; furthermore, an association with a significance of P = 0.045 was found with the PANSS negative symptoms scale. The absence of the Ser311Cys polymorphism on the DRD2 gene within the sample was also reported. In conclusion, it is noted that there is a statistically significant difference between the symptomatologic group, individuals with allele A / G SNP Taq1-B, and the group of individuals without the polymorphism. Even though the biological mechanisms behind this result are not understood, his study will serve as a basis for the development of future research related to this topic.

Association between dopamine receptor D2 genetic polymorphism TaqIA1 (C t) and susceptibility to alcohol dependence

Several studies are published, which investigated dopamine receptor 2 (DRD2) gene TaqIA polymorphism as ris factor for alcohol dependence (AD) with positive and negative association. 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 were performed. Eligible articles were identified through 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 measure.A total of 69 studies with 9,125 cases and 9,123 healthy controls were included in current meta-analysis. Results of present analysis showed significant association between DRD2 TaqIA polymorphism and AD risk using a 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 between In subgroup analysis, TaqIA polymorphism was not significantly associated with AD risk in Asian population under all genetic models, but in 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.