Actions of group i and group ii metabotropic glutamate receptor ligands on 5-hydroxytryptamine release in the rat cerebral cortex in vivo: differential roles in the regulation of central serotonergic neurotransmission

Abstract

We have previously shown that the release of central neurotransmitters can be modulated by the activation of Group I and Group II subtypes of G-protein-linked metabotropic glutamate (mGlu) receptors. To date, however, very little is known about the regulation of serotonergic neurotransmission by these receptor subtypes. In the present study, we have utilized in vivo intracerebral microdialysis to elucidate the roles of Group I and Group II mGlu receptors in the regulation of neuronal 5-hydroxytryptamine (5-HT) release in the frontal cortex of conscious, freely moving rats. Dialysate 5-HT was of neuronal origin with basal release showing strong calcium dependency and tetrodotoxin sensitivity and marked elevation following K +-induced depolarization. The broad-spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; 1–3 mM] did not significantly modify basal cerebrocortical 5-HT release. Similarly, the Group I mGlu receptor-specific agonist (RS)-3,5-dihydroxyphenylglycine [(RS)-3,5-DHPG; 1–3 mM] showed no marked effect on cortical dialysate 5-HT levels. To eliminate the possibility that these findings were the result of receptor desensitization, the effects of lower concentrations of (RS)-DHPG (100–300 μM) and shorter ligand exposure time (15 min) were also evaluated. Dialysate 5-HT levels remained unmodified by these manipulations. In comparison, the Group II mGlu receptor agonist, (2S,1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG-1; 500 μM), evoked a marked facilitation of release (approximately 150% of basal) which was fully reversed by the Group I/II antagonist, (S)-α-methyl-4-carboxyphenylglycine [(S)-MCPG; 3 mM]. The modulatory action of L-CCG-1 showed a bell-shaped concentration-response relationship. (S)-MCPG (3 mM) and the potent and selective mGlu 5 receptor antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 100 μM), when given alone, did not significantly modify 5-HT levels. The current data provide strong evidence to suggest that while the release of neuronal 5-HT in the rat frontal cortex is not subject to regulation by facilitatory Group I mGlu receptors, it may be positively modulated by activation of Group II mGlu receptors. Taken together with data from other studies, the present investigation lends emphasis to the notion that neuromodulation by mGlu receptors is a region-specific phenomenon and also proposes that the heterogeneous distribution of these receptors is neurone-specific in its complexity. The failure of (S)-MCPG alone to modify cortical 5-HT release suggests that Group II mGlu receptors do not tonically modulate serotonergic neurotransmission in the cerebral cortex but this does not preclude an important functional role for these receptors during pathological conditions when endogenous neurotransmitter levels become excessively elevated. The strategic development of new subtype-specific mGlu receptor ligands may provide novel therapeutic agents for the treatment of a range of neurological and psychiatric disorders.