Sensitization of cortical acetylcholine release by repeated administration of nicotine in rats

Rationale: The integrity of cortical cholinergic transmission is vital to attentional processing. A growing literature suggests that alterations in attentional processing accompany addictive drug use. This study examined the effects of acute and repeated administration of nicotine on cortical acetylcholine release. Objectives: The effects of repeated systemic nicotine administration on cortical acetylcholine (ACh) efflux in the frontal cortex were determined to test the hypothesis that repeated administration of nicotine results in a potentiated or sensitized increase in ACh efflux. Methods: Animals were injected with nicotine (0.4 mg/kg, i.p.) or vehicle twice daily for 4 days. Cortical ACh efflux was measured using repeated microdialysis sampling on four occasions: on day 1, during the first exposure to nicotine or vehicle, on day 5 during a final exposure to nicotine, on day 8 during a nicotine challenge, and again on day 10 following saline administration. Results: Acute nicotine administration on day 1 produced a 90% increase in cortical ACh efflux. Repeated exposure to nicotine resulted in a larger increase in cortical ACh efflux on day 5 (200%) and day 8 (210%) relative to ACh levels measured on day 1, and relative to animals that received vehicle during the initial treatment period. Cortical ACh efflux following acute nicotine administration was blocked by mecamylamine (1.0 mg/kg, i.p.). However, the sensitized efflux of cortical ACh on day 8 was only partially attenuated by mecamylamine (1.0 or 5.0 mg/kg, i.p.), suggesting a mecamylamine-insensitive component of the sensitized response to repeated nicotine administration. Conclusions: Repeated administration of nicotine results in a sensitized increase in cortical ACh release. Sensitized cortical ACh release may mediate, in part, the cognitive components of nicotine addiction.