The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice.

Abstract

Nicotine increases glutamate release in the ventral tegmental area and the nucleus accumbens, and thus enhances dopamine neurotransmission in the mesolimbic system that has been implicated in mediating the rewarding effects of drugs. Metabotropic glutamate receptors 5 (mGluR5) are found in the nucleus accumbens and may play a role in modulating the post-synaptic response to both glutamate and dopamine. The present study investigated the effects of the mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on intravenous nicotine self-administration in Wistar rats and DBA/2J mice. Rats were allowed to self-administer nicotine (0.01, 0.03 mg/kg per infusion) or respond for food on one of two fixed-ratio 5 schedules of reinforcement. Drug-naive mice were acutely exposed, in pairs, to nicotine (0, 0.016, 0.048, 0.16, 0.48 microg per infusion) self-administration under a fixed ratio 1 schedule of reinforcement, with one subject controlling the delivery of nicotine to both subjects in each pair. MPEP (1-9 mg/kg) dose-dependently reduced nicotine self-administration with no effect on food-maintained responding in the rats. Self-administration of nicotine was obtained only at the 0.048 microg per infusion dose by the mice, and administration of MPEP (5-20 mg/kg) decreased nicotine self-administration response rates in the mice. These results indicate that blockade of mGluR5 decreased nicotine self-administration in both rats and mice, and are consistent with findings showing a role of mGluR5 in cocaine self-administration. It is postulated that mGluR5 plays an essential role in mediating the reinforcing effects of nicotine, possibly but not exclusively, via modulation of mesolimbic dopaminergic neurotransmission.