Differential effects of NMDA and MGlu5 receptor antagonists injected in the nucleus accumbens shell and the ventral tegmental area on nicotinbe self-administration in rats

Manoranjan S. D’Souza, Ohio Northern University
Athina M. Markou, University of California - San Diego


Tobacco smoking, a preventable cause of worldwide morbidity and mortality, is partly attributed to the reinforcing properties of nicotine contained in tobacco. We previously reported that systemic administration of the N-methyl-D-aspartate (NMDA) receptor antagonist LY235959 or the mGluR5 antagonist 2-methyl-6-(phenylethynyl)- pyridine (MPEP) attenuated intravenous nicotine self-administration in rats. Intravenous nicotine administration increases glutamate release in the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). Based on these findings, we hypothesized that both compounds reduced the reinforcing effects of nicotine by acting on their respective receptors in the VTA and the NAcc shell. To test this hypothesis, we bilaterally microinjected LY235959 (0, 0.1, 1, 10 ng/0.5 µl/side) or MPEP (0, 10, 20, 40 µg/0.5 µl/side) directly into the NAcc shell or the VTA using a latin-square within-subjects design and assessed their effect on nicotine self-administration in rats. The results indicated that microinjection of MPEP in the NAcc shell or the VTA decreased nicotine self-administration in a dose-dependent manner (except 40 µg in the VTA that had no effect). LY235959 microinjection in the NAcc shell (10 ng/0.5 µl/side) increased nicotine self-administration, an effect rarely seen, while the same dose when injected into the VTA decreased nicotine self-administration. In conclusion, blockade of NMDA or mGlu5 receptors in the VTA decreased the reinforcing effects of nicotine indicating that activation of these receptors is critical in the reinforcing effects of nicotine. In contrast in the NAcc shell, blockade of NMDA and mGlu5 receptors had opposite effects on nicotine-self-administration. The increase in nicotine self-administration after microinjection of LY235959 in the NAcc shell is an interesting finding and suggests either of two alternative interpretations: (1) a decrease in the aversive effects of nicotine due to decreased activity of medium spiny neurons resulting from blockade of NMDA receptors; or (2) an increase in nicotine-seeking due to blockade of inhibitory inputs from the infralimbic cortex to the NAcc shell.