Separate GABA Afferents to Dopamine Neurons Mediate Acute Action of Opioids, Development of Tolerance, and Expression of Withdrawal

GABA release from interneurons in VTA, projections from the nucleus accumbens (NAc), and rostromedial tegmental nucleus (RMTg) was selectively activated in rat brain slices. The inhibition induced by μ-opioid agonists was pathway dependent. Morphine induced a 46% inhibition of IPSCs evoked from the RMTg, 18% from NAc, and IPSCs evoked from VTA interneurons were almost insensitive (11% inhibition). In vivo morphine treatment resulted in tolerance to the inhibition of RMTg, but not local interneurons or NAc, inputs. One common sign of opioid withdrawal is an increase in adenosine-dependent inhibition. IPSCs evoked from the NAc were potently inhibited by activation of presynaptic adenosine receptors, whereas IPSCs evoked from RMTg were not changed. Blockade of adenosine receptors selectively increased IPSCs evoked from the NAc during morphine withdrawal. Thus, the acute action of opioids, the development of tolerance, and the expression of withdrawal are mediated by separate GABA afferents to dopamine neurons. •GABA pathways to dopamine neurons are selectively sensitive to μ-opioid agonists•GABA pathways to dopamine neurons are selectively sensitive to adenosine agonists•Pathways that are most sensitive to opioids and adenosine are different•Morphine withdrawal is expressed selectively at terminals from nucleus accumbens Matsui et al. studied three opioid-sensitive GABA inputs to VTA dopamine neurons. The balance between initial sensitivity, development of tolerance, and expression of withdrawal were different for each pathway. Thus, different neuronal pathways regulate the three stages of opioid action.