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Motivational Effects of Methylphenidate are Associated with GABRA2 Variants Conferring Addiction Risk.

ABSTRACT: BACKGROUND:Variations in the GABRA2 gene, encoding ?2 subunits of GABAA receptors, have been associated with risk for addiction to several drugs, but the mechanisms by which variations in non-coding regions of GABRA2 increase risk for addictions are not understood. Mice with deletion of GABRA2 show deficits in the ability of psychostimulants to facilitate responding for conditioned reinforcers, offering a potential explanation. METHODS:We report human and mouse studies investigating a potential endophenotype underlying this association. Healthy human volunteers carrying either cocaine-addiction "risk" or "protective" GABRA2 single nucleotide polymorphism (SNPs) were tested for their subjective responses to methylphenidate, and methylphenidate's ability to facilitate conditioned reinforcement (CRf) for visual stimuli (CS+) associated with monetary reward. In parallel, methylphenidate's ability to facilitate responding for a visual CRf was studied in wildtype and ?2 knockout (?2(-/-)) mice. RESULTS:Methylphenidate increased the number of CS+ presentations obtained by human subjects carrying protective, but not risk SNPs. In mice, methylphenidate increased responding for a CS+ in wildtype, but not ?2(-/-) mice. Human subjects carrying protective SNPs felt stimulated, aroused and restless following methylphenidate, while individuals carrying risk SNPs did not. CONCLUSION:Human risk SNP carriers were insensitive to methylphenidate's effects on mood or in facilitating CRf. That mice with the gene deletion were also insensitive to methylphenidate's ability to increase responding for CRf, suggests a potential mechanism whereby low ?2-subunit levels increase risk for addictions. Circuits employing GABAA-?2 subunit-containing receptors may protect against risk for addictions.

SUBMITTER: Duka T

PROVIDER: S-EPMC4649050 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Motivational Effects of Methylphenidate are Associated with GABRA2 Variants Conferring Addiction Risk.

Duka Theodora T Dixon Claire I CI Trick Leanne L Crombag Hans S HS King Sarah L SL Stephens David N DN

Frontiers in behavioral neuroscience 20151118

<h4>Background</h4>Variations in the GABRA2 gene, encoding α2 subunits of GABAA receptors, have been associated with risk for addiction to several drugs, but the mechanisms by which variations in non-coding regions of GABRA2 increase risk for addictions are not understood. Mice with deletion of GABRA2 show deficits in the ability of psychostimulants to facilitate responding for conditioned reinforcers, offering a potential explanation.<h4>Methods</h4>We report human and mouse studies investigati ...[more]

PMID: 26635556

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Project description:Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems-level effects of methylphenidate in this population have not yet been described.To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.Randomized, placebo-controlled, before-after, crossover study.Clinical research center.Eighteen nonabstaining individuals with cocaine use disorders.Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects).Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems-level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire.Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections.These findings help elucidate the neural systems-level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently, remodel abnormal circuitry relevant to the pathophysiologic characteristics of cocaine addiction. In particular, the effects of methylphenidate within striatal and cortical pathways constitute a potentially viable mechanism by which methylphenidate could facilitate control of behavior in cocaine addiction.

Dataset Information

Motivational Effects of Methylphenidate are Associated with GABRA2 Variants Conferring Addiction Risk.

Publications

Motivational Effects of Methylphenidate are Associated with GABRA2 Variants Conferring Addiction Risk.

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