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VTA GABA(A) receptors mediate maladaptive disinhibition of dopamine release in the NAc ő a potential mechanism for increased risk taking behavior following adolescent voluntary alcohol intake (658.9)
Author(s) -
Schindler Abigail,
Tsusui Kimberly,
Clark Jeremy
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.658.9
Subject(s) - gabaa receptor , dopamine , ventral tegmental area , stimulation , dopamine receptor , neuroscience , receptor , muscimol , disinhibition , endocrinology , medicine , chemistry , psychology , pharmacology , dopaminergic
Alcohol is the most commonly abused drug among adolescents and shows the highest liability of all abused drugs. We have previously demonstrated that voluntary alcohol consumption by adolescent rats results in maladaptive risk‐taking behavior and phasic dopamine release in adulthood, as assessed by a probability discounting task and fast scan cyclic voltammetry (FSCV). These findings suggest that adolescent alcohol exposure‐induced changes in striatal dopamine release could bias choice by assigning greater value to the risky option, but the underlying mechanisms remain unknown. GABAA receptors located in the VTA are a potential candidate for mediating these effects. Using electrical stimulation of PPT glutamatergic afferents to VTA DA neurons, here we demonstrate that adult rats previously exposed to alcohol during adolescence show increased phasic dopamine release in the NAc, as compared to controls. PPT stimulation elicits GABAA receptor dependent current in VTA DA neurons, raising the possibility that adolescent alcohol intake produces this increased phasic dopamine release through downregulation of GABAA receptors on VTA DA neurons. Systemic administration of L‐838,417, a GABAA receptor α2, α3, and α5 subunit allosteric agonist, causes a dose‐dependent decrease in phasic DA release elicited by PPT stimulation in control rats, and this decrease is enhanced in rats exposed to alcohol during adolescence. Additionally, imaging flow cytometry was used to measure expression of GABAA receptor subunits on neurons of the ventral midbrain. Preliminary results suggest that GABAA receptor α3, but not α1, subunit surface expression is decreased following adolescent alcohol intake. Taken together, these results provide unique insight into the potential role that GABAergic modulation of dopamine neurons plays in the maladaptive risk taking behavior seen following adolescent alcohol exposure and highlights new potential therapeutic targets. Grant Funding Source : R01AA021121 and T32AA07455