Blockade of N-methyl-D-aspartate receptors in the nucleus accumbens shell and core has a differential effect on nicotine and food self-administration in rats

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


The reinforcing effects of nicotine are partly mediated by the mesolimbic dopaminergic system whose activity is closely regulated by excitatory glutamatergic neurotransmission at the level of both the ventral tegmental area (VTA) and the nucleus accumbens (NAcc). Nicotine increases glutamatergic transmission via presynaptic excitatory nicotinic receptors located on glutamatergic nerve terminals. Accordingly, previous work from our laboratory has shown that blockade of glutamatergic transmission via blockade of N-methyl-d-aspartate (NMDA) receptors in the VTA, using the competitive NMDA receptor antagonist LY235959, attenuated the reinforcing effects of nicotine, and thus decreased nicotine self-administration in rats. However, little is known about the role of NAcc NMDA receptors in nicotine reinforcement. Based on the above observations, we hypothesized that microinjection of the NMDA receptor antagonist LY235959 in the NAcc core and shell will decrease nicotine self-administration. To test this hypothesis, we assessed the effects of LY235959 (0, 1, 0.1, 1 & 10 ng/0.5 µl/side) injected bilaterally into the NAcc core or shell on nicotine and food self-administration in rats. Microinjections of LY235959 (10 ng/0.5 µl/side) in the NAcc shell (n=12) significantly increased nicotine self-administration, while there was no effect when LY235959 was injected into the NAcc core (n=6). In contrast, microinjection of the same doses of LY235959 in the NAcc core (n=8) or shell (n=8) dose-dependently attenuated food self-administration. Thus, our findings suggest that blockade of NMDA receptors in the NAcc core and shell has differential effects on food and nicotine reward. This differential effect is possibly due to activation of different circuits or cells by nicotine and food reward and is consistent with previously reported findings. Importantly, the differential results suggest that the increase in nicotine self-administration after microinjection of LY235959 in the NAcc shell is specific to nicotine and not a general increase in reward-seeking behavior. The results also suggest that NMDA receptors in the NAcc shell play a more important role compared to those in the core in mediating nicotine reward. In contrast, NMDA receptor activity in both the core and the shell is required for maintenance of food self-administration behavior. Finally, blockade of NMDA receptors in the NAcc shell resulted in an increase in nicotine self-administration behavior possibly either due to a decrease in the aversive effects of nicotine that may allow increased nicotine intake or due to an increase in nicotine-seeking behavior. Supported by the NIH grant DA11946 to AM.