Integrative Opioid-GABAergic Neuronal Mechanisms Regulating Dopamine Efflux in the Nucleus Accumbens of Freely Moving Animals

The nucleus accumbens (NAc) is a terminal region of mesocorticolimbic dopamine (DA) neuronal projections from the ventral tegmental area. Accumbal DA release is integrated by afferents from other brain regions and by interneurons, which involve a diversity of neurotransmitters and neuropeptides. These integrative processes, implicated in the pathobiology of neuropsychiatric disorders, are mediated via receptor subtypes whose relative roles in the regulation of accumbal DA release are poorly understood. Such complex interactions are exemplified by how selective activation of opioid receptor subtypes enhances accumbal DA efflux in a manner that is modulated by changes in neural activity through GABA receptor subtypes. This review delineates the roles of GABA and GABA receptors in GABAergic neural mechanisms in NAc that participate in delta- and mu-opioid receptor-mediated increases in accumbal DA efflux in freely moving rats, focusing on studies using in vivo brain microdialysis. First, we consider how endogenous GABA exerts inhibition of accumbal DA efflux through GABA receptor subtypes. We also consider possible intra-neuronal source of the endogenous GABA that inhibits accumbal DA efflux. As NAc contains GABAergic neurons that express delta- or mu-opioid receptors, inhibition of accumbal GABAergic neurons is a candidate for mediating delta- or mu-opioid receptor-mediated increases in accumbal DA efflux. Therefore, we provide a detailed analysis of the effects of GABA receptor subtype ligands on delta- and mu-opioid receptor-mediated accumbal DA efflux. Finally, we present an integrative model to explain the mechanisms of interaction among delta- and mu-opioid receptors, GABAergic neurons and DAergic neurons in NAc.