ACUTE STRESS OR CORTICOSTERONE ADMINISTRATION REDUCES RESPONSIVENESS TO NICOTINE - IMPLICATIONS FOR A MECHANISM OF CONDITIONED TOLERANCE

We have shown that conditioned tolerance develops to some of the behav ioral and endocrine effects of nicotine in rats. Other investigators h ave suggested that tolerance to multiple nicotine injections in mice m ay be due, in part, to elevated plasma corticosterone (CORT) levels, s ince repeated nicotine injections are associated with elevated CORT, c hronically elevated CORT reduces nicotine responsiveness and adrenalec tomy disrupts nicotine tolerance. Three experiments tested the feasibi lity of this hypothesis, as a mechanism for conditioned nicotine toler ance in rats, by determining whether acute administration of CORT or m anipulations that increase adrenocortical activity reduce nicotine res ponsiveness. In experiment 1, male rats were injected IP with CORT (1 mg/kg), vehicle (ETOH + distilled water) or no injection 10 min before nicotine (0.75 mg/kg, SC) and tested for nicotine-induced analgesia e very other day for 10 days. A significant reduction in withdrawal late ncies was obtained for CORT pretreated rats compared to animals given only nicotine. A similar reduction was produced by the vehicle pretrea tment, which itself induced all elevation of endogenous CORT. Experime nts 2 and 3 established that similar effects could be produced by dose s of CORT as low as 0.125 mg/kg or by exposure to a novel environment which also elevated CORT levels. Results also suggest that a condition ed release of endogenous CORT was triggered by stimuli associated with nicotine delivery. These data are consistent with the hypothesis that a conditioned release of CORT could contribute to the development of tolerance to some of nicotine's effects. The possibility that other ne uroendocrine mediators might be involved in addition to or instead of CORT, is also discussed.