On the Role of Nmda Receptor Subunits in the Acute and Chronic Effects of Nicotine

Nicotine is considered the main dependence-producing constituent in tobacco products. In analogy with other drugs of abuse, nicotine enhances dopamine (DA) neurotransmission within the mesocorticolimbic DA system. This increase in DA release is thought to be at least partially responsible for the reinforcing and dependence-producing effects of nicotine. However, accumulating evidence suggests that also glutamatergic neurotransmission is involved in the dependenceproducing effects of nicotine since nicotine also enhances the release of glutamate release in the mesocorticolimbic DA system, and glutamate receptor antagonists inhibit the nicotine-induced release of DA in the nucleus accumbens (NAcc). The aim of this study was to investigate how NMDA and AMPA receptor antagonists modulate the acute and chronic effects of nicotine on locomotor activity (LMA) and mesocorticolimbic DA release. In particular, we wanted to examine the possible role of NMDA receptor subunits in the stimulatory actions of nicotine following acute and chronic administration of the drug. Acute administration of nicotine produced a dose-dependent increase in LMA and DA release in the NAcc. Administration of the novel AMPA receptor antagonist ZK200775 and the competitive NMDA receptor antagonist CGP39551 attenuated the effects of nicotine. In contrast and unexpectedly, the NR2B subunit selective NMDA receptor antagonist, Ro 25-6981 potentiated the acute effects of nicotine on LMA (without producing stereotypies) as well as on DA release in the NAcc. Chronic administration of nicotine resulted in the development of behavioral sensitization and nicotine-conditioned locomotor stimulation. Behavioral sensitization developed two days prior to the onset of the conditioned response. When Ro 256981 was given to naïve rats at a dose, which by itself had no effect on LMA, in rats chronically treated with nicotine, it significantly increased LMA without inducing stereotypies. Moreover, the same dose of Ro 25-6981 had no effect on DA release in the medial prefrontal cortex (mPFC) whereas a trend toward increased DA release was noted in the NAcc. In addition, Ro 25-6981 potentiated nicotine-induced DA release in the mPFC but not in the NAcc. Chronic administration of nicotine exposure caused no changes in the expression levels of NR2A or NR2B mRNA in the prefrontal cortex (PFC) or ventral striatum (VStr) but Western blot revealed that there was an upregulation of the NR2B subunit protein but not NR2A subunit protein in the PFC with no corresponding changes in the VStr. Taken together, our data suggest that both AMPA and NMDA receptors are involved in the acute effects of nicotine on LMA and NAcc DA release. However, whereas a non-selective blockade of NMDA receptors inhibits the acute effects of nicotine on LMA and NAcc DA release, a selective blockade of the NR2B subunit enhances nicotine's acute effects. In addition, chronic nicotine treatment upregulates the NR2B subunit in the PFC but not in the VStr suggesting that chronic nicotine exposure induces regionally selective neuroadaptative changes in the composition of NMDA receptor subunits. These observations are of potential interest not only for our understanding of the neurochemical mechanisms involved in nicotine dependence but also for some psychiatric and neurodegenerative disorders known to be associated with disturbances in the interplay between dopaminergic and glutamatergic neurotransmission.