Once weekly administration of nicotine produces long-lasting locomotor sensitization in rats via a nicotinic receptor-mediated mechanism

Rationale: Chronic nicotine administration results in dynamic changes in neuronal function, expressed as behavioral sensitization in animals and addiction in smokers. Objectives: The present study was undertaken to determine whether once-weekly nicotine injection produces sensitization to the locomotor-activating properties of nicotine as a result of nicotinic receptor activation. Methods: Once weekly for 6 weeks, rats were administered (s.c.) two saline injections or saline and nicotine (0.35 mg/kg), and locomotor activity was monitored. Rats remained in the home cage for 21 days, and subsequently were injected with the appropriate treatment to determine whether sensitization persisted. Rats were also injected with saline or mecamylamine (1.2 mg/kg) followed by saline or nicotine once weekly for 6 weeks to determine the effect of mecamylamine and whether it inhibited nicotine-induced hyperactivity. A separate group was injected with saline and nicotine once weekly for 4 weeks; on week 5, mecamylamine and nicotine were administered to determine whether mecamylamine inhibited the expression of sensitization. Separate groups were injected with mecamylamine and nicotine once weekly for 5 weeks or 6 weeks; on week 6 or week 9, respectively, saline and nicotine were injected to determine whether mecamylamine inhibited the initiation of sensitization. Results: Sensitization to the locomotor-activating properties of nicotine developed following four nicotine injections across a 28-day period and persisted following 21 days of no drug treatment. Mecamylamine did not alter activity but attenuated both the initiation and expression of sensitization. Conclusions: Nicotinic receptor activation following once-weekly nicotine administration produces long-lasting behavioral sensitization, suggesting that even infrequent nicotine exposure initiates neuroadaptive processes associated with nicotine addiction.