INTERACTING PRESYNAPTIC KAPPA-OPIOID AND GABA(A) RECEPTORS MODULATE DOPAMINE RELEASE FROM RAT STRIATAL SYNAPTOSOMES

The presynaptic regulation of stimulated dopamine release from superfu sed rat striatal synaptosomes by opioids and gamma-aminobutyric acid ( GABA) was studied. It was found that in addition to dopamine D2 autore ceptors, calcium-dependent K+-stimulated [H-3]dopamine release was inh ibited through activation of a homogeneous populaiton Of kappa-opioid receptors in view of the potent inhibitory effect of the kappa-selecti ve agonist U69,593 (EC50 0.2 nM) and its antagonism by norbinaltorphim ine. Neither mu- nor delta-selective receptor agonists affected releas e of [H-3]-dopamine. In addition, GABA potently inhibited the evoked [ H-3]dopamine release (EC50 0.4 nM) through activation of GABA(A) recep tors in view of the GABA-mimicking effect of muscimol, the sensitivity of its inhibitory effect to picrotoxin and bicuculline, and the absen ce of an effect of the GABA(B) receptor agonist baclofen. In the prese nce of a maximally effective concentration of GABA, U69,593 did not in duce an additional release-inhibitory effect, indicating that these re ceptors and the presynaptic D2 receptor are colocalized on the striata l dopaminergic nerve terminals. The excitatory amino acid agonists N-m ethyl-D-aspartate and kainate, as well as the cholinergic agonist carb achol, stimulated [H-3]dopamine release, which was subject to kappa-op ioid receptor-mediated inhibition. In conclusion, striatal dopamine re lease is under regulatory control of multiple excitatory and inhibitor y neurotransmitter by activation of colocalized presynaptic receptors for excitatory amino acids, acetylcholine, dopamine, dynorphins, and G ABA within the dopaminergic nerve terminals. Together, these receptors locally control ongoing dopamine neurotransmission.