Differential effects of the mGlu2/3 receptor agonist LY379268 on self-administered and experimenter-administered nicotine-induced increases in nucleus accumbens shell dopamine in rats
The mesolimbic dopaminergic system plays a critical role in the reinforcing effects of drugs of abuse, including nicotine. Glutamatergic transmission also plays an important role in the reinforcing effects of nicotine, as nicotine activates the mesolimbic dopaminergic system by activating excitatory nicotinic receptors on glutamatergic nerve terminals. Metabotropic glutamate (mGlu) 2/3 receptors that negatively regulate glutamatergic transmission are critically involved in the reinforcing effects of drugs of abuse, including nicotine. We previously showed that systemic (s.c.) or direct administration into the nucleus accumbens (NAcc) or the ventral tegmental area of the mGlu2/3 receptor agonist LY379268 (1 mg/kg, s.c.) decreased nicotine self-administration and cue-induced nicotine-seeking behavior in rats. Further, chronic nicotine self-administration resulted in downregulation of mGlu2/3 receptor function in key mesocorticolimbic brain areas. We hypothesize here that LY379268 decreased the reinforcing effects of nicotine by attenuating nicotine-induced increase in NAcc shell dopamine. Using in vivo microdialysis, the present study examined the effect of systemic LY379268 (1 mg/kg, s.c.) pretreatment on NAcc shell dopamine after an experimenter-administered nicotine (0.4 mg/kg, s.c., base) injection in both drug-naïve rats and in rats with a history of intravenous nicotine self-administration. In addition, we also examined the effect of LY379268 pretreatment on NAcc shell dopamine after a single intravenous self-infusion of nicotine (0.06 mg/kg/infusion) in rats with a history of intravenous nicotine self-administration. Systemic LY379268 (1 mg/kg) pretreatment abolished NAcc shell dopamine increase after nicotine self-administration in nicotine-experienced rats. However, pretreatment with LY379268 (1 mg/kg) had no effect on the experimenter-administered nicotine-induced increase in dopamine in the NAcc shell in either nicotine-naïve or nicotine-experienced rats. These data indicate that the mGlu2/3 receptor agonist LY379268 decreases the primary reinforcing effects of self-administered nicotine and the motivational impact of nicotine-associated stimuli by blocking the nicotine-induced activation of the mesolimbic dopaminergic system. Further, these data demonstrate that mGlu2/3 receptors play a more critical role in regulating the dopamine response to nicotine in the presence of stimuli associated with nicotine as compared to nicotine alone.