Research Grants Program Office

Recent evidence implicates endogenous pituitary adenylyl cyclase activating polypeptide (PACAP) in the aversive effect of nicotine. In the present study, we assessed if nicotine-induced conditioned place preference (CPP) or affective signs of nicotine withdrawal would be altered in the absence of PACAP and if there were any sex-related differences in these responses. Male and female mice lacking PACAP and their wild-type controls were tested for baseline place preference on day 1, received conditioning with saline or nicotine (1 mg/kg) on alternate days for 6 days and were then tested for CPP the next day. Mice were then exposed to four additional conditioning and were tested again for nicotine-induced CPP 24 hr later. Controls were conditioned with saline in both chambers and tested similarly. All mice were then, 96 hr later, challenged with mecamylamine (3 mg/kg), and tested for anxiety-like behaviors 30 min later. Mice were then, 2 hr later, forced to swim for 15 min and then tested for depression-like behaviors 24 hr later. Our results showed that male but not female mice lacking PACAP expressed a significant CPP that was comparable to their wild-type controls. In contrast, male but not female mice lacking PACAP exhibited reduced anxiety- and depression-like behaviors compared to their wild-type controls following the mecamylamine challenge. These results suggest that endogenous PACAP is involved in affective signs of nicotine withdrawal, but there is a sex-related difference in this response.