Dataset Information

The ?-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

ABSTRACT: We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals.This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocaine (40?mg, IV), and subjective responses were assessed 15?min before receiving an infusion and at 5?min intervals for the subsequent 20?min. The rs1048101 variant of the ?1A-adrenoceptor (ADRA1A) gene was genotyped and it was evaluated whether the Cys to Arg substitution at codon 347 in exon 2 (Cys347Arg) moderated the magnitude of the subjective effects produced by cocaine.Thirty (46%) participants were found to have the major allele CC genotype and 35 (44%) carried at least one minor T-allele of rs1048101 (TT or TC genotype). Individuals with the CC genotype showed greater responses for 'desire' (P<0.0001), 'high' (P<0.0001), 'any drug effect' (P<0.0001), 'like cocaine' (P<0.0001), and 'likely to use cocaine if given access' (P<0.05) with experiment-wise significance.This study indicates that the ADRA1A genotype could be used to identify individuals for whom acute cocaine exposure may be more rewarding and by inference may result in greater difficulty in establishing and/or maintaining abstinence from cocaine.

SUBMITTER: Shorter D

PROVIDER: S-EPMC4970930 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

Shorter Daryl D Nielsen David A DA Hamon Sara C SC Nielsen Ellen M EM Kosten Thomas R TR Newton Thomas F TF De La Garza Richard R

Pharmacogenetics and genomics 20160901 9

<h4>Objectives</h4>We examined whether a functional variant of the ADRA1A gene moderated cocaine-induced subjective effects in a group of cocaine-dependent individuals.<h4>Methods</h4>This study was a within-participant, double-blind, placebo-controlled inpatient human laboratory evaluation of 65 nontreatment-seeking, cocaine-dependent [Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV)] individuals aged 18-55 years. Participants received both placebo (saline, IV) and cocain ...[more]

PMID: 27379509

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Project description:BackgroundPreclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic α(1) receptor antagonist doxazosin on the positive subjective effects of cocaine.MethodsThirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind.ResultsDoxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of "high", "stimulated", "like cocaine", "desire cocaine", "any drug effect", and "likely to use cocaine if had access" (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of "stimulated", "like cocaine", and "likely to use cocaine if had access" (p<.05). There were trends for doxazosin to reduce ratings of "stimulated", "desire cocaine", and "likely to use cocaine if had access" (p<.10).ConclusionsMedications that block noradrenergic α₁ receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.Trial registrationClinicaltrials.gov NCT01062945.

Project description:AimsThe social environment strongly influences individual mental health. Individuals with strong social support systems tend to experience higher levels of well-being, lower levels of psychological distress and exhibit fewer psychiatric symptoms. However, there is a significant degree of individual variability as to the extent to which social support is beneficial to overall mental health. From a neurobiological perspective, it is suggested that the social hormone, oxytocin, may moderate the favorable effects of social interaction. To explore this possibility, we evaluated oxytocin genotype, social support and psychological health in a group of individuals diagnosed with DSM-IV alcohol dependence.MethodsThe associations between OXT genotype, social support and psychological health were analyzed in data from 269 adults diagnosed with DSM-IV alcohol dependence (25% female) admitted into residential treatment programs and outpatient centers in Warsaw, Poland.ResultsIn line with past observations, we noted that psychiatric distress scores were negatively correlated with social support. Extending these observations, we uncovered a significant moderating effect of OXT genotype (rs2740210) on the relationship between social support and psychiatric distress. While G carriers displayed the predicted negative relationship between social support and psychiatric distress, T homozygotes failed to exhibit such a relationship.ConclusionGenetically driven variation in oxytocin system functioning may influence the degree to which the beneficial effects of social support are felt in this population. These results have direct clinical relevance as enhancing social engagement to improve mental health may prove to be a less effective strategy in some patients owing to intrinsic factors.Short summaryThe associations between oxytocin genotype, social support, and psychological health were analyzed in data from 269 adults diagnosed with DSM-IV alcohol dependence. A significant moderating effect of OXT genotype (rs2740210) on the relationship between social support and psychiatric distress was detected.

Dataset Information

The ?-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

Publications

The α-1 adrenoceptor (ADRA1A) genotype moderates the magnitude of acute cocaine-induced subjective effects in cocaine-dependent individuals.

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