Nucleus accumbens dopamine release modulation by mesolimbic GABA A receptors—an in vivo electrochemical study

Abstract

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 GABA A 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 GABA A receptor antagonist bicuculline. In contrast, the GABA B agonist baclofen decreased, while 2-OH-saclofen (a GABA B antagonist) increased DA release in the NAcc. However, when VTA GABA B 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 GABA A receptors may be co-localized on both DA neurons and non-DA (GABAergic) interneurons in the VTA, with the effects of GABA A 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 GABA A receptors appear to play a complex role in mediating drug reinforcement, depending upon the dynamic functional state of GABA A receptors on both tegmental DA and non-DA neurons.