Kappa opioid receptor activation in the nucleus accumbens inhibits glutamate and GABA release through different mechanisms

Through their actions in the nucleus accumbens (NAc), kappa opioid (KOP) receptors and their endogenous ligand, dynorphin, modify behaviors associated with the administration of drugs of abuse and are regulated by exposure to such drugs. Despite their demonstrated behavioral significance, the synaptic actions of KOP receptor ligands in the NAc are not clearly understood. Using whole-cell voltage-clamp recordings of NAc medium spiny neurons, we have found that, in addition to suppressing glutamate release, the KOP receptor agonist U69593 also inhibits GABA release. Interestingly, the mechanism of inhibition of the release of glutamate differs from that controlling GABA. U69593 reduces the frequency of Ca2+-independent miniature excitatory postsynaptic currents, but not miniature inhibitory postsynaptic currents. Furthermore, while the U69593 inhibition of GABAergic transmission is blocked by the N-type Ca2+ channel blocker omega-CgTx, the inhibition of excitatory glutamatergic transmission by U69593 is unaffected by N-type Ca2+ channel blockade. These results indicate that KOP receptor activation inhibits GABA release by reducing Ca2+ influx, but inhibits glutamate release at a step downstream of Ca2+ entry.