Characterization of pre- and post-synaptic metabotropic glutamate receptor-mediated inhibitory responses in substantia nigra dopamine neurons

Abstract

Two inhibitory responses mediated by both pre- and post-synaptic metabotropic glutamate receptors (mGluRs) were investigated in dopamine neurons of the substantia nigra using whole-cell patch recordings. (2R,4R)-APDC, a group II mGluR agonist, and L-2-amino-4-phosphonobutyrate (L-AP4), a group III mGluR agonist, reversibly suppressed the amplitude of excitatory postsynaptic currents (EPSCs). However, (S)-3,5-DHPG, a group I mGluR agonist, exhibited less inhibitory action on the EPSCs. LY341495, a highly potent group II mGluR antagonist, antagonized the broad spectrum mGluR agonist, 1S,3R-ACPD-induced suppression of EPSCs. In acutely dissociated dopamine neurons, glutamate (Glu) in the presence of CNQX and AP-5 evoked an outward current accompanied by an increase in K(+) conductance. (S)-3,5-DHPG, but not (2R,4R)-APDC or L-AP4, also induced an outward current. Glu-induced outward current (I(Glu-out)) was partially inhibited by LY367385, a selective mGluR1 antagonist, but not by MPEP, a selective mGluR5 antagonist. Ryanodine and cyclopiazonic acid blocked the I(Glu-out). In the presence of caffeine, Glu failed to induce a current. Charybdotoxin, but not apamin or iberiotoxin, inhibited the I(Glu-out). Taken together, both group II and III mGluRs are mainly involved in the presynaptic inhibition of Glu release to dopamine neurons, while group I mGluRs, including at least mGluR1, participate in the hyperpolarization of dopamine neurons mediated by the opening of charybdotoxin-sensitive Ca(2+)-activated K(+) channels.