Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmacology & Toxicology

First Advisor

Thomas H. Leahey

Second Advisor

John A. Rosecrans


Current concepts concerning nicotine's central nervous system (CNS) mechanism(s) of action suggest that this drug is producing its effects via an interaction at nicotiniccholinergic receptors (nAChRs) which open a membrane cation channel. Following initial opening of the channel, nicotine appears to induce a rapid desensitization of the nAChRs, closing the channel and resulting in a cessation of nicotine's effects. Research presented here will provide evidence of this secondary desensitization process in vivo by demonstrating nicotine's ability to induce acute tolerance in the discriminative stimulus (DS) paradigm. The ability of nicotine to elicit DS control of behavior was significantly reduced via challenge doses of (800, 1200, and 1600 ugjkg, s.c.) of nicotine administered 60-180 minutes prior to the training dose (400 ugjkg, s.c.). Eight out of twenty rats demonstrated this phenomena, with time and dose varying, suggesting that these effect may be contingent upon the individual rat studied. It appears that we have found a means of investigating cellular mechanisms in vivo using operant behavior.


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