D2 Receptor Gene Research Articles

Association of the DRD4 exon III and 5-HTTLPR VNTR polymorphisms with substance abuse in Jordanian Arab population

Genetic variations in the dopamine D4 receptor (DRD4) gene and the serotonin transporter (SLC6A4) gene are involved in the aetiology of substance abuse disorder (SUD). The main aim of this study is to evaluate the genetic association of DRD4 (48 bp-VNTR) and SLC6A4 (rs25531 and 5-HTTLPR VNTR) gene polymorphisms with SUD susceptibility among the Jordanian Arab population. This study included 500 SUD patients and 500 healthy matched controls. The VNTR Genetic polymorphisms of DRD4 and SLC6A4 genes were genotyped using conventional polymerase chain reaction (PCR). While, the rs25531 SNP was genotyped using PCR-restriction fragment length polymorphism (PCR-RFLP) technique. The genetic association was analysed using different statistical analyses including chi-square, Fisher exact test and one way ANOVA test. The DRD4 exon III VNTR polymorphism was associated with SUD significantly in case of alleles 4, 7 and genotype 7/7 (P = 0.004, 0.0005 and 0.01, respectively). While, there was no genetic association between the 5-HTTLPR (LL, LS, SS), rs25331 (AA, AG, GG) and tri-allelic (SASA, LASG, LASA, LALG, LALA) genotypes (P = 0.26, 0.71 and 0.52, respectively) and SUD. Moreover, using multinomial regression analysis, the homozygous 7/7 and 2/2 VNTR genotypes of DRD4 gene were nominally significantly associated with a lower risk of addiction (OR = 0.285 with P = 0.003 and OR = 0.447 with P = 0.031, respectively) after adjusting for other covariates. Our findings showed that 4 and 7 repeats and the genotype 7/7 of DRD4 exon III VNTRs polymorphism are involved in the aetiology of SUD among Jordanian population in compared to the 5-HTTLPR polymorphisms.

34.2 DOPAMINE D4 RECEPTORS IN ANIMAL MODELS OF NEURODEVELOPMENTAL DISORDERS

Previous research suggests that the exon 3 variable number of tandem repeat (VNTR) polymorphism of the human dopamine D4 receptor gene (DRD4) contributes to ADHD and other psychiatric phenotypes. Animal studies may show how differences in D4 expression and function lead to these phenotypes and whether environmental factors influence behavioral outcomes.

THE GENETIC BASIS OF DEPRESSION

Alterations in the monoaminergic neurotransmission systems are suspected to be involved in the etiology of neuropsychiatric disorders, including depression. The role of these pathways in the risk of developing depressive symptoms during childhood or adolescence is still not completely clear. This study sought to identify putative genetic factors in genes of serotonergic and dopaminergic systems modulating the level of manifestation of depressive symptoms in children and adolescents. We analyzed 170 single nucleotide polymorphisms (SNPs) in 21 candidate dopaminergic and serotonergic genes in a non-clinical sample of 410 Costa Rican participants of ages between 7 and 18 years, assessing the severity of depressive symptoms through the Child Depression Inventory (CDI). Genotypic and haplotypic associations, as well as epistatic effects, were examined. A significant interaction effect was detected between rs1039089 in conjunction with rs877138 located upstream of the dopamine D1 receptor (DRD1) and the dopamine D2 receptor (DRD2) genes respectively, although no evidence was found for any single variant or haplotype related to a differential liability. This newly described genetic interaction among putative regulatory regions of dopamine receptors could affect the level of manifestation of depressive symptoms through an imbalance of D1-D2 heteromers and modulation of cognitive processes.

Regulation of adenosine A2A receptor gene expression in a model of binge eating in the amygdaloid complex of female rats.

Pharmacological treatment approaches for eating disorders, such as binge eating disorder and bulimia nervosa, are currently limited. Using a well-characterized animal model of binge eating, we investigated the epigenetic regulation of the A2A Adenosine Receptor (A2AAR) and dopaminergic D2 receptor (D2R) genes. Gene expression analysis revealed a selective increase of both receptor mRNAs in the amygdaloid complex of stressed and restricted rats, which exhibited binge-like eating, when compared to non-stressed and non-restricted rats. Consistently, pyrosequencing analysis revealed a significant reduction of the percentage of DNA methylation but only at the A2AAR promoter region in rats showing binge-like behaviour compared to the control animals. Focusing thus on A2AAR agonist (VT 7) administration (which inhibited the episode of binge systemically at 0.1 mg/kg or intra-central amygdala (CeA) injection at 900 ng/side) induced a significant increase of A2AAR mRNA levels in restricted and stressed rats when compared to the control group. In addition, we observed a significant decrease in A2AAR mRNA levels in rats treated with the A2AAR antagonist (ANR 94) at 1 mg/kg. Consistent changes in the DNA methylation status of the A2AAR promoter were found in restricted and stressed rats after administration of VT 7 or ANR 94. We confirm the role of A2AAR in binge eating behaviours, and we underline the importance of epigenetic regulation of the A2AAR gene, possibly due to a compensatory mechanism to counteract the effect of binge eating. We suggest that A2AAR activation, inducing receptor gene up-regulation, could be relevant to reduction of food consumption.

Parsing out the role of dopamine D4 receptor gene (DRD4) on alcohol-related phenotypes: A meta-analysis and systematic review.

Genetics account for moderate variation of individual differences in developing alcohol use disorder (AUD), but it is unclear which genetic variations contribute to AUD risk. One candidate gene investigated due to its association with AUD is the dopamine D4 receptor gene (DRD4), which contains a 48-base pair variable number tandem repeat (VNTR) in exon 3 of its coding region. To date, no quantitative synthesis of the published literature on the effects of DRD4 VNTR variation on alcohol-related phenotypes has been conducted. MEDLINE, Embase, Web of Science, and PsycInfo were searched for studies that reported on alcohol craving, alcohol consumption, severity of AUD, and case-control (AUD versus no diagnosis of AUD) studies in DRD4L (seven repeats or more) carriers compared with DRD4S (six repeats or less) homozygotes. Random-effects meta-analysis was used for all analyses. A pooled sample size of 655 to 13,360 of 28 studies were included. Compared with DRD4S homozygotes, DRD4L carriers had increased number of drinking days (SMD: 0.205; 95% CI: 0.008 to 0.402), binge drinking days (SMD: 0.217; 95% CI: 0.0532 to 0.380), and severity of AUD (SMD: 0.143; 95% CI: 0.028to0.259). There was no difference between DRD4 VNTR genotypes on drinks per drinking day, largest number of drinks per day/occasion, and case-control analysis. It was not possible to conduct a meta-analysis of the craving data, but a systematic review of this literature found mixed results on DRD4 VNTR genotype effect. The present meta-analysis suggests DRD4 VNTR variation may be a risk factor for problematic alcohol use. Our findings are limited, however, by the absence of ancestry data from studies included in our analysis, precluding our ability to adjust for population stratification. Due to the likelihood of type I error in candidate gene approaches, our work highlights the critical need for studies with larger and more inclusive samples that account for sex and genetic ancestry to fully understand this relationship.

Functional analysis of 5 upstream polymorphic variations of the human dopamine D1 receptor gene.

Functional analysis of 5 upstream polymorphic variations of the human dopamine D1 receptor gene.

Conditioned place preferences induced by hearing song outside the breeding season relate to neural dopamine D1 and cannabinoid CB1 receptor gene expression in female European starlings (Sturnus vulgaris)

The affective state induced by sensory stimuli changes to adaptively modify behaviors that are critical for survival and reproduction. In European starlings, during the spring breeding season, male courtship song is rewarding to females, but only to those that possess resources that are necessary for reproduction (i.e., nesting sites). In fall, starling song is non-sexual and proposed to maintain flocks. This suggests that in fall it may be adaptive for females to be rewarded by fall rather than spring, courtship song. We used a conditioned place preference (CPP) test to evaluate song-induced affective state in fall condition females and quantitative real-time PCR to measure expression of genes that modulate affective state (CB1 endocannabinoid and D1 dopamine receptors) in brain regions that were previously implicated in song-induced reward (i.e., the medial preoptic nucleus (mPOA) and ventromedial hypothalamus (VMH)). Fall condition females developed an aversion to a place that had been paired with playback of both male fall and courtship song, indicating that in general male song induces a negative affective state outside the breeding season. Song-induced aversion was stronger in birds conditioned towards an initial place preference. For mPOA, CB1 receptor expression correlated positively with fall and spring song-induced CPP. D1 receptor expression correlated negatively with fall (but not spring) song-induced CPP, and the ratio of CB1 to D1 receptor expression correlated positively with fall (but not spring) song-induced CPP. These correlations suggest that interactions between D1 and CB1 receptors in mPOA may play a role in modifying affective responses to song.

Association of dopamine D2 receptor gene polymorphisms with prolactin levels related to risperidone treatment: A systematic review and meta-analysis.

Dopamine D2 receptor (DRD2) polymorphisms are inconsistently associated with elevated prolactin levels related to risperidone treatment. The aim of this systematic review and meta-analysis was to investigate whether DRD2 polymorphisms could modulate prolactin levels in patients treated with risperidone. Three electronic databases (PubMed, EMBASE and the Cochrane Library) were searched for studies investigating the effect of DRD2 polymorphisms on prolactin levels in patients treated with risperidone until May 2018. Summary standard mean differences (SMDs) and 95% confidence intervals (CIs) were calculated with Hedges' g tests for effect estimates using random effects models. The heterogeneity, sensitivity, univariable meta-regression, subgroup analyses and publication biases were calculated. After initially identifying 886 studies, 772 patients from eight studies were included. Summary SMDs indicated that compared with A1 non-carriers, Taq1A A1 carriers did not have different risperidone-related prolactin levels (SMD: 0.13; 95% CI: -0.18 to 0.43; P=0.423) among patients with schizophrenia (SCZ; SMD: 0.07; 95% CI: -0.14 to 0.29; P=0.505) or among those without SCZ (SMD: 0.16; 95% CI: -0.39 to 0.71; P=0.562). There was no significant difference between Del carriers and Del non-carriers with regard to risperidone-related prolactin levels (SMD: -0.00; 95% CI: -0.59 to 0.58; P=0.996). In an Asian subgroup analysis, we also noted that compared with Taq1A A1A2 carriers, Taq1A A1A1 carriers had lower prolactin levels (SMD: -0.34; 95% CI: -0.66 to -0.02; P=0.040). However, there was no significant difference in prolactin levels between A1A1 carriers and A2A2 carriers (SMD: -0.27; 95% CI: -0.60 to 0.05; P=0.098), or between A2 carriers and A2 non-carriers (SMD: 0.29; 95% CI: -0.01 to 0.59; P=0.059). Based on univariable meta-regression analyses, the effects of publication year, study design, ethnicity, comparison groups and study quality could bias the identified association of DRD2 Taq1A with risperidone-related prolactin levels. The findings of this study suggest that there is no significant difference between Taq1A A1 carriers and non-A1 carriers with regard to risperidone-related prolactin levels. As there were few A1 homozygotes, large prospective studies with robust designs are still needed to investigate whether A1A1 could affect risperidone-related prolactin levels in the Asian population.

Association of DRD2, 5-HTTLPR, and 5-HTTVNTR Gene Polymorphisms With Posttraumatic Stress Disorder in Tibetan Adolescents: A Case-Control Study.

Earthquake exposure is a source of stress, yet only a minority of survivors experience clinically meaningful disturbance in psychological function. Genetic epidemiological research has found that posttraumatic stress disorder (PTSD) symptoms are associated with genetic factors. Further research to reveal which genetic loci relate to the development of PTSD is warranted. We investigated the relationships between PTSD and the dopamine D2 receptor ( DRD2) gene Taq I polymorphism and the serotonin transporter gene ( SCL6A4) polymorphisms 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) and 5-HTTVNTR in 565 adolescent earthquake survivors. PTSD-positive adolescents were identified using the PTSD Checklist-Civilian Version and the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders 4. Genotypes were analyzed using the polymerase chain reaction-restriction fragment length polymorphism analysis. The Pearson χ2 test was used to investigate the differences in genotype and allele frequencies between case and control groups. Binary logistic regression analysis was performed to identify possible influencing factors for PTSD. The DRD2 Taq I and 5-HTTVNTR polymorphisms had statistically significant effects on PTSD, while 5-HTTLPR did not. Specifically, the DRD2 Taq I A1 allele was highly positively correlated with PTSD, whereas the 10 allele of 5-HTTVNTR was negatively correlated. These data suggest that the DRD2 Taq I and 5-HTTVNTR genotypes moderate sensitivity to stress and the expression of emotional disturbance involving PTSD symptoms. These findings have important implications for PTSD etiology as well as for both primary prevention and treatment strategies.

Neurophysiology and genetics of burning mouth syndrome.

Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS. Forty-five BMS patients (43 women), mean age 62.5years, and 32 healthy controls (30 women), mean age 64.8years, participated. Patients estimated pain intensity, interference, suffering and sleep with Numeric Rating Scale. Blink reflex tests of the supraorbital (SON), mental (MN) and lingual (LN) nerves, and thermal quantitative sensory testing were done. The results were analysed with ANOVA. DRD2 gene 957C>T polymorphism was determined in 31 patients, and its effects on neurophysiologic and clinical variables were analysed. Cool (p=0.0090) and warm detection thresholds (p=0.0229) of the tongue were higher in BMS patients than controls. The stimulation threshold for SON BR was higher in patients than in controls (p=0.0056). The latencies of R2 component were longer in BMS patients than in controls (p=0.0005) at the SON distribution. Habituation of SON BR did not differ between the groups. The heat pain thresholds were highest (p=0.0312) in homozygous patients with 957TT, who also reported most interference (p=0.0352) and greatest suffering (p=0.0341). Genotype 957CC associated with sleep disturbances (p=0.0254). Burning mouth syndrome patients showed thermal hypoesthesia within LN distribution compatible with small fibre neuropathy. The DRD2 957C>T genotype influences perception and experience of BMS pain. The results confirm earlier findings of neuropathic pain in BMS. The DRD2 957 C>T genotype influences perception and experience of clinical pain in BMS.

Polymorphism TaqIA Gen Dopamine D2 Receptor In Men Aged Start From 40 Years Old With Metabolic Syndrome Compared To Non Metabolic Syndrome

Introduction : Metabolic syndrome involves heritability , genetic , bad diet and lack of physical activity One cause of the Metabolic Syndrome is a genetic abnormality in the dopamine D2 receptor gene that causes Reward Deficiency Syndrome . Aim: To investigate the relationship between polymorphisms of the dopamine D2 receptor gene Taq1A in men starting from 40 years of age with metabolic syndrome compared to those without metabolic syndrome. Methods: This research was done as an unpaired analytical research using case control design The research subject is stored DNA isolates originating from metabolic syndrome 21 and 21 are non metabolic syndrome Thermal Cycle process performed on isolates DNA using PCR techniques with applications located on a 310 bp band with a 2 % agarose gel , then the application in digestion with enzyme Taq1A ( New England Biolabs ®Inc ) and there are variant polymorphism ( T / C 310 bp , 180 bp , 130 bp ) , ( C / C 180 bp , 130 bp ) , ( T / T 310 bp ) and analyzed statistically using x² test , odds ratio. Result: Based on the metabolic syndrome X ² test was found genotype T / C at most ( 47.6 % ) , T / T ( 19.1 % ) , C / C ( 33.3 % ) with a value of p = 0.500 with a significance of p < 0 , 05 In no metabolic syndrome T / C ( 61.9 % ) , T / T ( 9.5 % ) , C / C ( 28.6 % ) with a value of p = 0.457 with a significance of p < 0.05. Based on the distribution of allele no significant relationship. Conclusion: Based on the results of the study didn’t relate to the frequency distribution of genotype and allele distribution Taq1A polymorphisms of the dopamine D2 receptor gene in men aged from 40 years with the metabolic syndrome than those without metabolic syndrome

Dopamine D4 receptor gene expression plays important role in extinction and reinstatement of cocaine-seeking behavior in mice

Dopamine D4 receptor (DRD4) dysregulation is associated with a variety of behaviors including novelty-seeking, approach avoidance, and ADHD. DRD4 has also been shown to interact with the environment to produce changes in behavior and longevity. The present study sought to examine the role of DRD4 on cocaine-seeking behavior in the conditioned place preference (CPP) test and determine its effects on extinction and reinstatement in adult wild-type (WT), heterozygous (HT), and knockout (KO) mice. Results revealed that all mice, regardless of sex or genotype, developed a similar acquisition for a cocaine place preference. Female DRD4 KO mice failed to extinguish their preference for the cocaine-paired chamber following the extinction period. Male DRD4 KO mice failed to reinstate their preference after a priming dose following successful extinction. No differences in locomotor activity were observed within drug treatment conditions due to genotype, and female mice displayed reduced locomotor activity during CPP conditioning compared to male mice. The observed effects illustrate the role DRD4 gene expression has on extinction and reinstatement, but not acquisition, of cocaine-seeking behavior.

Dopamine D4 Receptor Gene Exon III VNTR Variant Influences Smoking Status in Turkish Population.

Dopaminergic gene variants may affect nicotine dependence through their possible impact on the dopamine reward pathway. The purpose of this study is to investigate the relationship between the variable number tandem repeat (VNTR) variant in exon III of the Dopamine D4 receptor (DRD4) gene and genetic predisposition of smoking status in a Turkish population. We performed a study comparing 154 subjects as the smoker group, and 111 subjects as the non-smoker group. Genotyping for the DRD4 VNTR variant was performed using a PCR method. There was a significant difference between smoker and non-smoker groups regarding the distribution of the alleles and genotypes of the DRD4 gene (p=0.000, p=0.000, respectively). The 2R allele was higher in the non-smoker group compare to the smoker group (p=0.000). We found that the 2/7 and 4/9 genotypes were more common in smokers than non-smoker group (p=0.037, p=0.028, respectively) while 2/4 genotype was more prevalent in non-smokers than smokers (p=0.000). When the number of repeat alleles (48 bp) are accepted as short (S) if six or less, and as long (L) if seven or more, it was found that the frequency of S/S genotype of the DRD4 VNTR variant was lower in the smoker group and S/L genotype was higher in the smoker group (p=0.006, p=0.006, respectively). The subjects carrying the S/L genotype have a 2.25-fold increased risk for smoking than a non-smoker. The results indicated that the subjects carrying DRD4 exon III VNTR S/L genotype have a risk for smoking status in a Turkish population.

Associations between the dopamine D4 receptor gene polymorphisms and personality traits in elite athletes.

Personality traits and temperament may affect sports performance. Previous studies suggest that dopamine may play an important role in behavior regulation and physical exercise performance. The aim of this study is to determine associations between dopamine D4 receptor gene (DRD4 Ex3) polymorphisms and personality traits (such as neuroticism, extraversion, openness, agreeability and conscientiousness) in elite combat athletes. A total of 302 physically active, unrelated, self-reported Caucasian participants were recruited for this study. The participants consisted of 200 elite male combat athletes and 102 healthy male participants (control group). For personality trait measurements, the NEO Five-Factor Personality Inventory (NEO-FFI) and the State-Trait Anxiety Inventory questionnaires were used. For the genetic assays, blood was collected and all samples were genotyped using the real-time PCR method. A 2 x 3 factorial ANOVA revealed statistically significant differences on the Openness NEO Five Factor Inventory scale for both examined factors, i.e. sport status and genetics DTD4 Ex3. Combat athletes achieved higher scores on the Conscientiousness NEO-FFI scale when compared to controls (7.18 vs 5.98). On the other hand, combat athletes scored lower on the Openness scale in comparison with control group (4.42 vs. 4.63). Subjects with the DRD4 Ex3 s/s genotype had lower results on the openness scale in comparison with participants with the DRD4 Ex3 s/1 genotype (4.01 vs. 4.57) and higher DRD4 Ex3 1/1 genotype (4,01 vs. 3,50). In conclusion, we found an association between the dopamine D4 receptor gene in variable number tandem repeat (VNTR) polymorphisms and athletic status for two NEO-FFI factors: Openness and Conscientiousness. The DRD4 exon 3 polymorphism may be associated with the selected personality traits in combat athletes, thereby modulating athletes’ predisposition to participate in high risk sports.

M68 - THE RELATIONSHIP BETWEEN FUNCTIONAL DOPAMINE D2 RECEPTOR HAPLOTYPES AND COGNITIVE OUTCOMES, AS MEDIATED BY REGIONAL BRAIN STRUCTURE: A COMPARISON OF CONTROL, AT-RISK, AND BIPOLAR DISORDER SUBJECTS

Background Bipolar Disorder (BD) is a complex and highly heritable mood disorder associated with a range of cognitive deficits across all illness states. Previous research has demonstrated associations between the dopamine D2 receptor gene (DRD2) and BD diagnosis, structural and functional brain changes, and cognitive dysfunction. Specific SNPs impacting DRD2 function have been identified: rs1800497 (Taq1A1, minor T allele) is associated with reduced striatal D2R dopamine binding; and rs1076560 and rs2283265 (minor A/T alleles) are associated with alternative splicing of DRD2 exon 6, resulting in increased expression of DRD2-short mRNA compared to DRD2-long isoform, and reduced inhibition of glutamate release. The present study adopted a cognitive-neurogenic approach to explore the mediating role of brain structure in the relationship between DRD2 functional haplotypes and cognitive outcomes. Methods Participants comprised 26 BD cases (BD-I or BD-II), 62 at-risk subjects (unaffected first-degree relatives of BD probands), and 55 control subjects with 3 T MRI, genetic and cognitive data. DRD2 haplotypes were defined by three functional SNPs (rs1800497, rs1076560, rs2283265). Cortical thickness, surface area and volume were extracted for three functionally defined regions of interest (ROIs) that were parcellated on the basis of resting state functional connectivity data – Dorsal Attention (DA), Ventral Attention (VA), and Fronto-Parietal (FP). Working memory and attention were assessed using Repeatable Battery for Assessment of Neuropsychological Status (RBANS), and intelligence (IQ) was determined using Wechsler Abbreviated Scale of Intelligence (WASI). A series of simple and multiple mediation models were implemented using SPSS PROCESS macro. These models predicted the effects of the functional DRD2 haplotype on working memory, attention and intelligence, as independently and jointly mediated by cortical area, thickness and volume in the three functionally defined ROIs. Results The frequency of CCG homozygotes versus TAA carriers was significantly higher in at-risk subjects compared to controls (freq=0.758 vs 0.564, p=0.013) with a trend in BD (freq=0.692, p=0.1). In the control group, CCG homozygotes exhibited an increase in RBANS attention scores as a result of the mediating effects of DA area and volume (of 1.6 and 1.7 standard deviations). Simple mediation effects were also observed in the control group for IQ and RBANS immediate memory in the absence of a significant total effect. In contrast, simple mediation effects were not apparent in the slightly larger at-risk group nor the BD group. While multiple mediation models reinforced many simple mediation effects observed in controls, an additional mediation effect was observed in the BD group – TAT haplotype carriers exhibited a 0.6 SD decrease in RBANS attention scores as a result of the mediating effects of FP volume. Discussion The DRD2 mediation effects observed in controls were absent in the at-risk and BD groups, suggesting that the normally ameliorative effect of the CCG haplotype on cognitive outcomes is either negated by other genetic and familial risk factors for BD, or is mediated by alternate brain structures. Additionally, evidence is provided for the reversal of typically observed DRD2 effects on cognitive outcomes by the significant mediation effect for the BD group in the multiple mediation model of attention, where carriers of the TAT haplotype demonstrated improved attention.

P.1.21 Selective regulation of cb1 and d2 receptor genes transcription by perinatal delta-9-tetrahydrocannabinol exposure

P.1.21 Selective regulation of cb1 and d2 receptor genes transcription by perinatal delta-9-tetrahydrocannabinol exposure

Different roles of Rac1 in the acquisition and extinction of methamphetamine-associated contextual memory in the nucleus accumbens.

Rationale: Repeated methamphetamine (METH) exposure induces long-term cognitive deficits and pathological drug-associated memory that can be disrupted by manipulating memory reconsolidation and extinction. The nucleus accumbens (NAc) is the key region of the brain reward system and predominantly consists of two subtypes of medium spiny neurons (MSNs) based on the expression of D1 or D2 dopamine receptors (D1-MSNs or D2-MSNs). Spine structural plasticity in the NAc is critical for the acquisition, reconsolidation and extinction of drug-associated memory. However, the molecular mechanisms underlying METH-associated memory and spine remodelling in each type of MSNs in the NAc remain unknown. Here, we explored whether Rac1 in the NAc mediates METH-associated contextual memory and spine remodelling.Methods: Pharmacological and genetic manipulations of Rac1 were used to investigate its role during the acquisition, reconsolidation and extinction of METH-associated contextual memory. Recombinant adeno-associated viruses expressing mCherry under the control of the dopamine D1 receptor gene promoter (Drd1-mCherry) or dopamine D2 receptor gene promoter (Drd2-mCherry) were used to specifically label D1-MSNs or D2-MSNs.Results: Using viral-mediated gene transfer, we demonstrated that decreased Rac1 activity was required for the acquisition of METH-associated contextual memory and the METH-induced increase in thin spine density, whereas increased Rac1 signalling was important for the extinction of METH-associated contextual memory and the related elimination of thin spines. Moreover, the increase of dendritic spines was both found in D1-MSNs and D2-MSNs during the acquisition process, but extinction training selectively decreased the spine density in D1-MSNs. Interestingly, Rac1 was responsible for METH-induced spine plasticity in D1-MSNs but not in D2-MSNs. Additionally, we found that microinjection of a Rac1 inhibitor or activator into the NAc was not sufficient to disrupt reconsolidation, and the pharmacological activation of Rac1 in the NAc facilitated the extinction of METH-associated contextual memory. Regarding cognitive memory, decreased Rac1 activity improved the METH-induced impairment in object recognition memory.Conclusion: Our findings indicate that Rac1 plays opposing roles in the acquisition and extinction of METH-associated contextual memory and reveal the cell-specific role of Rac1 in METH-associated spine remodelling, suggesting that Rac1 is a potential therapeutic target for reducing relapse in METH addiction and remediating METH-induced recognition memory impairment.

Tardive dyskinesia: Who gets it and why

Tardive dyskinesia (TD) is a potentially permanent movement disorder resulting from chronic use of dopamine receptor blocking agents (DRBA). Identified risk factors include the type of antipsychotic agent, being greater for those of first generation antipsychotics (FGA), the duration of illness and cumulative dose of DRBA and advanced age. Female sex and African and Caucasian ethnicity are additional potential risk factors. Because only a subset of people taking DRBA's develops TD, genetics may play a role. Susceptibility gene candidates include those involved in DRBA metabolism and the targets or receptors of DRBA's. Although met with conflicting data, the following genes may be involved with TD development: the cytochrome P450 gene CYP2D6, involved with metabolism of most antipsychotics, Dopamine D2 and D3 receptor genes, serotonin 2A and 2C receptor genes, vesicular monoamine transporter 2 (VMAT 2) gene, involved with intracellular neurotransmitter packaging, and the manganese superoxide dismutase (MnSOD) gene, an antioxidant enzyme. Heparan sulfate proteoglycan 2 (HSPG 2) gene is another potential gene involved with development of TD. The pathogenesis of TD is unknown, however there are three main theories proposed: dopamine receptor supersensitivity resulting from chronic dopamine receptor blockade, oxidative stress and maladaptive synaptic plasticity each of which is discussed further in this article.Tardive dyskinesia (TD) is a potentially permanent and disabling adverse effect from certain medications. By definition TD is the insidious onset of rhythmic, repetitive, stereotypic movements of the face, mouth and tongue, often with involvement of the trunk and extremities that occur as a result of dopamine receptor blocking agents (DRBA) [1]. The term tardive refers to the delayed onset of the disorder. The mean prevalence of TD is estimated to be 25.3% in psychiatric patients taking antipsychotics [2]. Compared to the number of people taking these drugs, TD represents a minority. TD is a potentially permanent condition; stopping the offending agent does not always alleviate the condition. Therefore, prevention of TD by avoiding DRBA's if at all possible is ideal. However, there is no apparent way to predict who will develop TD and there are some cases in which DRBA's are necessary for treatment of chronic conditions. As TD has been present since the development of DRBA's, possible risk factors for its development have been studied. Solmi et al. (2018) [3] have written a comprehensive review on this subject.

Cultural variation in the gray matter volume of the prefrontal cortex is moderated by the dopamine D4 receptor gene (DRD4).

Recent evidence suggests a systematic cultural difference in the volume/thickness of prefrontal regions of the brain. However, origins of this difference remain unclear. Here, we addressed this gap by adopting a unique genetic approach. People who carry the 7- or 2-repeat (7/2-R) allele of the dopamine D4 receptor gene (DRD4) are more sensitive to environmental influences, including cultural influences. Therefore, if the difference in brain structure is due to cultural influences, it should be moderated by DRD4. We recruited 132 young adults (both European Americans and Asian-born East Asians). Voxel-based morphometry showed that gray matter (GM) volume of the medial prefrontal cortex and the orbitofrontal cortex was significantly greater among European Americans than among East Asians. Moreover, the difference in GM volume was significantly more pronounced among carriers of the 7/2-R allele of DRD4 than among non-carriers. This pattern was robust in an alternative measure assessing cortical thickness. A further exploratory analysis showed that among East Asian carriers, the number of years spent in the U.S. predicted increased GM volume in the orbitofrontal cortex. The present evidence is consistent with a view that culture shapes the brain by mobilizing epigenetic pathways that are gradually established through socialization and enculturation.

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 μg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.