N-methyl-D-aspartate receptor-mediated neurotransmission in the nucleus accumbens shell or core regulates nicotine reinforcement and nicotine-seeking behavior in rats
The reinforcing effects of nicotine are partly mediated by dopaminergic neurons which originate in the ventral tegmental area (VTA) and terminate in the nucleus accumbens (NAc). Both the VTA and the NAc receive excitatory glutamatergic terminals which originate from the prefrontal cortex and other corticolimbic nuclei. Glutamatergic neurotransmission in the VTA and NAc is mediated by several glutamatergic receptors, including the N-methyl-D-aspartate (NMDA) receptors. Nicotine increases the activity of the dopaminergic neurons predominantly by increasing glutamatergic transmission in the VTA. Blockade of NMDA receptors in the VTA decreases nicotine self-administration. Nicotine also increases glutamate levels in the NAc. However, little is known about the role of NMDA receptors in the NAc shell and core in nicotine intake and nicotine-seeking behavior. Thus, the present study assessed the effects of bilateral administration of the competitive NMDA receptor antagonist LY235959 (0, 0.1, 1 & 10 ng/0.5 µl/side) into the NAc shell or core on intravenous nicotine self-administration, in separate cohorts of rats for each brain site. Additional groups of rats were used to assess the effects of the same microinjections on cue-induced reinstatement of nicotine seeking. LY235959 (10 ng/0.5 µl/side) microinjections into the NAc shell (n=7-8/group), but not the core (n=7-10/group), significantly increased nicotine self-administration under both fixed- and progressive-ratio schedules of reinforcement. Furthermore, LY235959 microinjections (10 ng/0.5 µl/side; n=8/group) into either the NAc core or shell significantly increased reinstatement of cue-induced nicotine-seeking behavior compared to reinstatement after vehicle administration, with the effects being more prounouced in the core. Taken together, these data suggest that blockade of NMDA receptors in either the shell or core increases nicotine intake and/or nicotine-seeking behavior. NMDA receptors in the NAcc are predominantly located on cell bodies of inhibitory GABAergic neurons and a few of these neurons project to the VTA. Blockade of these NAc NMDA receptors diminishes the inhibitory output from the NAcc to the VTA. Therefore, a possible mechanism for the findings of the present study could be that blockade of NAc NMDA receptors increases the activity of VTA dopaminergic neurons by decreasing the inhibitory output from the NAc, an action that ultimately leads to increased nicotine intake and nicotine-seeking behavior. In conclusion, NMDA-mediated glutamatergic transmission in the NAc shell and core critically regulates nicotine intake and nicotine-seeking behavior in rats.
D’Souza MS, Markou AM. N-methyl-D-aspartate receptor-mediated neurotransmission in the nucleus accumbens shell or core regulates nicotine reinforcement and nicotine-seeking behavior in rats. Program No. 796.07/II15. 2011 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2011. Online.