Differential involvement of ventral tegmental GABAA and GABAB receptors in the regulation of the nucleus accumbens dopamine response to stress

Abstract: Evidence indicates that dopamine (DA) transmission in nucleus accumbens (NAcc) is modulated by glutamate (GLUT) projections from medial prefrontal cortex (PFC) to NAcc and the ventral tegmental area (VTA). Local NMDA receptor blockade in NAcc has previously been shown to enhance the DA stress response in this region as well as in the VTA. This raises the possibility that the NAcc DA stress response is regulated by GLUT acting at NMDA receptors located on NAcc GABA output neurons that project to the VTA where GABA is known to regulate DA cell activity. Thus, in the present study, we used voltammetry to examine the effects of intra-VTA administration of GABAA and GABAB agonists and antagonists on restraint stress-induced increases in NAcc DA. The results show that local VTA GABAB receptor activation with baclofen (0.01, 0.1 and 1.0 nmol) dose-dependently inhibited the NAcc DA stress response whereas GABAB receptor blockade with phaclofen had the opposite effect, resulting in a dose-dependent potentiation of the stress response. A similar potentiation of the NAcc DA stress response was observed following VTA GABAA receptor blockade with bicuculline, but only at the highest dose (1.0 nmol). Interestingly, intra-VTA injection of the GABAA receptor agonist, muscimol, at the lowest dose (0.01 nmol) but not at the higher doses (0.1 or 1.0 nmol) also potentiated the NAcc DA stress response, suggesting an action mediated primarily at GABAA receptors located on non-DA neurons. These results indicate that the NAcc DA stress response is regulated by GABA afferents to VTA DA cells and that this action is differentially mediated by GABAA and GABAB receptors. The data suggest that the relevant GABAB receptors are located on DA neurons whereas the GABAA receptors are located on GABA interneurons and perhaps also on DA cells. The present findings are also consistent with the idea that the corticofugal GLUT input to NAcc indirectly regulates stress-induced DA release in this region through the GABA feedback pathway to VTA. [Copyright &y& Elsevier]