Dataset Information

Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial.

ABSTRACT: Dopamine (DA) signaling regulates many aspects of Alcohol Use Disorder (AUD). However, clinical studies of dopaminergic medications, including the DA partial agonist aripiprazole (APZ), have been inconsistent, suggesting the possibility of a pharmacogenetic interaction. This study examined whether variation in DA-related genes moderated APZ effects on reward-related AUD phenotypes. The interacting effects of APZ and a variable number tandem repeat (VNTR) polymorphism in DAT1/SLC6A3 (the gene encoding the DA transporter (DAT)) were tested. In addition, interactions between APZ and a genetic composite comprising the DAT1 VNTR and functional polymorphisms in catechol-O-methyltransferase (COMT), DRD2, and DRD4 were evaluated. Ninety-four non-treatment-seeking individuals with AUD were genotyped for these polymorphisms, randomized to APZ (titrated to 15?mg) or placebo for 8 days, and underwent an fMRI alcohol cue-reactivity task (day 7; n=81) and a bar lab paradigm (day 8). Primary outcomes were alcohol cue-elicited ventral striatal (VS) activation and the number of drinks consumed in the bar lab. DAT1 genotype significantly moderated medication effects, such that APZ, relative to placebo, reduced VS activation and bar-lab drinking only among carriers of the DAT1 9-repeat allele, previously associated with lower DAT expression and greater reward-related brain activation. The genetic composite further moderated medication effects, such that APZ reduced the primary outcomes more among individuals who carried a larger number of DAT1, COMT, DRD2, and DRD4 alleles associated with higher DA tone. Taken together, these data suggest that APZ may be a promising AUD treatment for individuals with a genetic predisposition to higher synaptic DA tone.

SUBMITTER: Schacht JP

PROVIDER: S-EPMC5916367 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial.

Schacht Joseph P JP Voronin Konstantin E KE Randall Patrick K PK Anton Raymond F RF

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20171206 6

Dopamine (DA) signaling regulates many aspects of Alcohol Use Disorder (AUD). However, clinical studies of dopaminergic medications, including the DA partial agonist aripiprazole (APZ), have been inconsistent, suggesting the possibility of a pharmacogenetic interaction. This study examined whether variation in DA-related genes moderated APZ effects on reward-related AUD phenotypes. The interacting effects of APZ and a variable number tandem repeat (VNTR) polymorphism in DAT1/SLC6A3 (the gene enc ...[more]

PMID: 29362512

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Project description:BackgroundHuman laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory.MethodsNon-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm.ResultsMultilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2 = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes.ConclusionsNeuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Project description:Background: Left cervical vagus nerve stimulation (l-VNS) is an FDA-approved treatment for neurological disorders including epilepsy, major depressive disorder, and stroke, and l-VNS is increasingly under investigation for a range of other neurological indications. Traditional l-VNS is thought to induce therapeutic neuroplasticity in part through the coordinated activation of multiple broadly projecting neuromodulatory systems in the brain. Recently, it has been reported that striking lateralization exists in the anatomical and functional connectivity between the vagus nerves and the dopaminergic midbrain. These emerging findings suggest that VNS-driven activation of this important plasticity-promoting neuromodulatory system may be preferentially driven by targeting the right, rather than the left, cervical nerve. Objective: To compare the effects of right cervical VNS (r-VNS) vs. traditional l-VNS on self-administration behavior and midbrain dopaminergic activation in rats. Methods: Rats were implanted with a stimulating cuff electrode targeting either the right or left cervical vagus nerve. After surgical recovery, rats underwent a VNS self-administration assay in which lever pressing was paired with r-VNS or l-VNS delivery. Self-administration was followed by extinction, cue-only reinstatement, and stimulation reinstatement sessions. Rats were sacrificed 90 min after completion of behavioral training, and brains were removed for immunohistochemical analysis of c-Fos expression in the dopaminergic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), as well as in the noradrenergic locus coeruleus (LC). Results: Rats in the r-VNS cohort performed significantly more lever presses throughout self-administration and reinstatement sessions than did rats in the l-VNS cohort. Moreover, this appetitive behavioral responding was associated with significantly greater c-Fos expression among neuronal populations within the VTA, SNc, and LC. Differential c-Fos expression following r-VNS vs. l-VNS was particularly prominent within dopaminergic midbrain neurons. Conclusion: Our results support the existence of strong lateralization within vagal-mesencephalic signaling pathways, and suggest that VNS targeted to the right, rather than left, cervical nerve preferentially activates the midbrain dopaminergic system. These findings raise the possibility that r-VNS could provide a promising strategy for enhancing dopamine-dependent neuroplasticity, opening broad avenues for future research into the efficacy and safety of r-VNS in the treatment of neurological disease.

Dataset Information

Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial.

Publications

Dopaminergic Genetic Variation Influences Aripiprazole Effects on Alcohol Self-Administration and the Neural Response to Alcohol Cues in a Randomized Trial.

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