Nucleus accumbens dopamine release modulation by mesolimbic GABAA receptors-an in vivo electrochemical study.
The role of GABA receptors in regulating the mesolimbic dopamine (DA) system and drug reinforced behaviors has not been well characterized. Using fast-cyclic voltammetry, the effects of specific GABA receptor modulation on DA release in the nucleus accumbens (NAcc) and heroin self-administration (SA) behavior was investigated. The GABAA agonist muscimol, administered either intravenously or directly into the ventral tegmental area (VTA), significantly increased DA release in the NAcc in 7 of the 10 rats tested. DA release decreased in the remaining three rats; both effects were blocked by pretreatment with the GABAA receptor antagonist bicuculline. In contrast, the GABAB agonist baclofen decreased, while 2-OH-saclofen (a GABAB antagonist) increased DA release in the NAcc. However, when VTA GABAB receptors were previously activated or inactivated by microinjections of baclofen or 2-OH-saclofen, systemic injections of muscimol caused an inhibition of NAcc DA release. These results suggest that GABAA receptors may be co-localized on both DA neurons and non-DA (GABAergic) interneurons in the VTA, with the effects of GABAA determined by the net effect of both direct inhibition and indirect disinhibition of DA neurons. Finally, although a DA releaser, muscimol was neither self-administered in drug naive rats, nor did it substitute for heroin in rats previously trained to self-administer heroin, suggesting that GABAA receptors appear to play a complex role in mediating drug reinforcement, depending upon the dynamic functional state of GABAA receptors on both tegmental DA and non-DA neurons.
Neuroscience Graduate Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D004563:Electrochemistry; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D008032:Limbic System / Q000378:metabolism*; D008297:Male; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000502:physiology*; D012646:Self Administration
D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D001418:Baclofen; D004298:Dopamine; C057491:2-hydroxysaclofen