Nicotine has a permissive role on the activation of metabotropic glutamate 5 receptors coexisting with nicotinic receptors on rat hippocampal noradrenergic nerve terminals.

The existence of metabotropic glutamate receptors (mGluRs) on hippocampal noradrenergic nerve terminals and their interaction with coexisting nicotinic acetylcholine receptors (nAChRs) were investigated in superfused rat synaptosomes using [(3)H]-noradrenaline ([(3)H]-NA) release as a readout. The selective agonist of group I mGluRs, (S)-3,5-dihydroxyphenylglycine (DHPG), inactive on its own, acquired ability to release [(3)H]-NA when added together with (-)-nicotine. The effect of DHPG was prevented by 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of mGluR5, but not by 7-(hydroxyimino)cyclopropane[b]chromen-1-carboxylate ethyl ester (CPCCOEt), selective antagonist of mGluR1. The [(3)H]-NA release evoked by (-)-nicotine plus DHPG was totally abrogated by the nAChR antagonist mecamylamine. Veratrine mimicked the permissive role of (-)-nicotine on the activation of mGluR5 mediating [(3)H]-NA release. The mGluR5-mediated component of the [(3)H]-NA release provoked by DHPG plus (-)-nicotine was blocked by xestospongin C, a selective antagonist of inositoltrisphosphate (IP(3)) receptors. It can be concluded that (i) release-enhancing mGluRs of subtype 5 exist on hippocampal noradrenergic axon terminals; (ii) activation of mGluR5 to mediate IP(3)-dependent NA release requires activation of depolarizing nAChRs coexisting on the same terminals.