In the midbrain, dopamine neurons can release dopamine somatodendritically. This results in an inhibitory postsynaptic current (IPSC) within adjacent dopamine cells that occurs by the activation of inhibitory D2 autoreceptors. Kappa, but not mu/delta, opioid receptors inhibit this IPSC. The aim of the present study was to determine the mechanism by which κ-opioid receptors inhibit the dopamine IPSC. In both the ventral tegmental area (VTA) and substantia nigra compacta (SNc) the κ-receptor agonist U69593 inhibited the IPSC, but not the current induced by the exogenous iontophoretic application of dopamine. The endogenous peptide dynorphin A (1-13) also inhibited IPSCs in the VTA and SNc, but also the dopamine iontophoretic current in the VTA. Although both kappa agonists induced a postsynaptic outward current in the VTA, the current induced by dynorphin was dramatically larger. This suggests that the decrease in iontophoretic dopamine current was the result of occlusion. Occlusion alone, however, could not completely account for suppression of the IPSC. The kappa opioid inhibition of the IPSC was not affected by global increases or decreases in dopamine cell activity within the slice. These findings suggest that, although kappa opioid receptors can hyperpolarize dopamine neurons, they also suppress dopamine release by direct actions at the release site. The results thus demonstrate both pre- and postsynaptic actions of kappa receptor agonists. The actions of dynorphin indicate that VTA dopamine cells are selectively regulated by kappa receptors.
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