Effects of medial prefrontal cortical injections of GABA receptor agonists and antagonists on the local and nucleus accumbens dopamine responses to stress.

Abstract

Stress stimulates dopamine (DA) release in nucleus accumbens (NAcc) but will do so more strongly in medial prefrontal cortex (PFC). Evidence indicates, however, that the cortical DA response to stress acts to dampen the concurrent increase in NAcc DA release. In the present study, we used voltammetry to investigate the role of PFC GABA in regulating the NAcc DA response to stress. The results of Experiment 1 show that the NAcc stress response is inhibited following bilateral cortical microinjections of baclofen (GABAB receptor agonist). While phaclofen (GABAB receptor antagonist) blocked the effect of baclofen, it had no significant effect of its own. Intra-PFC injections of muscimol (GABAA receptor agonist) and bicuculline (GABAA receptor antagonist) had no effect on the DA stress response in NAcc. In Experiment 2, we explored the possibility that GABA influences the NAcc DA stress response indirectly by modulating stress-induced DA release in PFC. None of the drugs tested had an effect on the PFC stress response at a dose (1 nmol) that produced reliable effects on the NAcc stress response. At an order of magnitude higher dose, however, locally applied phaclofen and muscimol enhanced and attenuated, respectively, the DA stress response in PFC. These results were validated in Experiment 3 by showing that intra-PFC injections of GBR-12395 (DA uptake blocker) and quinpirole (D2/D3 receptor agonist) dose-dependently enhanced and inhibited, respectively, the local DA stress response. Together, these findings indicate that increased GABA transmission in PFC exerts an inhibitory influence on the NAcc DA response to stress, and that this action is mediated primarily but not exclusively by GABAB receptors which may be located both on cortical output neurons and on DA terminals.