Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) microinfusions into the nucleus accumbens shell or ventral tegmental area attenuate the reinforcing effects of nicotine in rats

Systemic administration of the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was previously shown to selectively attenuate nicotine self-administration without affecting food-maintained responding in rats. Glutamatergic neurotransmission in the ventral tegmental area (VTA) and nucleus accumbens (NAcc) shell plays an important role in the reinforcing effects of nicotine. To determine the brain sites that may mediate the systemic effects of MPEP on nicotine self-administration, the present study investigated the effects of MPEP microinfusions into the VTA or the NAcc shell on nicotine and food self-administration in separate groups of rats. Administration of low MPEP doses (0, 0.5, 1, and 2 mu g/0.5 mu l/side) microinfused into the NAcc shell had no effect on nicotine self-administration, whereas higher MPEP doses (0, 10, 20, and 40 mu g/0.5 mu l/side) microinfused into the NAcc shell dose-dependently attenuated nicotine self-administration without affecting food-maintained responding. Microinfusions of MPEP into the VTA (0, 10, 20, and 40 mu g/0.5 mu l/side) significantly decreased both nicotine and food self-administration at 20 mu g/0.5 mu l/side but did not affect responding for either reinforcer at 40 mu g/0.5 mu l/side. This lack of effect of 40 mu g/0.5 mu l/side MPEP on either nicotine or food self-administration when administered into the VTA may be attributable either to actions of MPEP at presynaptic mG1u5 receptors or at targets other than mG1u5 receptors. Importantly, anatomical control injections 2 mm above the NAcc shell or the VTA using the most effective MPEP dose in the two regions did not result in attenuation of nicotine self-administration. In conclusion, MPEP microinfusions in the VTA or NAcc shell attenuates the reinforcing effects of nicotine possibly via blockade of mG1u5 receptors located in these regions. (C) 2011 Elsevier Ltd. All rights reserved.