Previous studies have shown that the prior administration of metabotropic glutamate receptor 5 (MGluR5) receptor antagonists inhibit responding for nicotine in an intravenous self-administration experiment. However, recent studies in this laboratory have shown that an mGluR5 receptor antagonist, MPEP (2-methyl-6-(phenylethynyl)-pyridine), also attenuates contextually-conditioned responding evoked by cues associated with the delivery or availability of nicotine. Thus, the results to date do not provide unequivocal evidence that the effects of mGluR5 receptor antagonists on responding for nicotine reflect a direct functional interaction between the antagonists and nicotine per se. This study employed in vivo microdialysis to test the hypothesis that the prior administration of the mGluR5 receptor antagonist, MPEP, inhibits a neural response to nicotine, increased dopamine (DA) overflow in the nucleus accumbens, implicated in directly in nicotine reinforcement. The results confirmed that prior administration of MPEP (2.5 mg/kg and 5 mg/kg IP) dose-dependently reduced responding for nicotine in a self-administration experiment. The higher dose caused complete inhibition of responding in a majority of the animals tested. MPEP injections, over the same dose range, also inhibited the effects of nicotine on DA overflow in the shell and core subdivisions of the rat nucleus accumbens. It is concluded that the data support the hypothesis that, in addition to their putative role in contextually-conditioned responding for nicotine, mGluR5 receptors are also implicated the primary reinforcing properties of the drug which depend upon increased DA overflow in the nucleus accumbens.
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