Sensitization to Cocaine: Behavioral and Genetic Characterization

Odom, Linda Ann, Sensitization to Cocaine: Behavioral and Genetic Characterization. Doctor of Philosophy (Pharmacology). April 1998, 141 pages, 2 tables, 23 figures, 89 references. Conditioned associations between environmental context and cocaine effects may play a significant role in acquisition and maintenance of cocaine dependence. Conditioning may also contribute significantly to cocaine sensitization, a leftward shift in the cocaine dose-response curve that is attributable to cocaine pre-exposure. Both studies examined the sensitization of cocaine’s behavioral effects after one or four prior exposures to cocaine in two distinct environments, allowing evaluation of the acquisition and magnitude of sensitization to cocaine and the contribution of conditioning to sensitization. An extinction component was added to the second study to allow determination of persistence of context-dependent sensitization in C57BL/6 and DBA/2 mice. The purpose of the first study was to fully characterize the quantity and quality of the sensitized behavioral response to cocaine in Swiss Webster mice and to determine parameters for sensitization in the second study. Results of this study indicated that pairing cocaine to the testing environment resulted in a leftward shift of the dose-response curves for both horizontal and stereotypy measures and a concurrent decrease in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on stereotypy. The multivariate behavior profile indicated that the sensitized response to cocaine was best observed in response to 1 to 5 mg/kg cocaine, and that the conditioned response elicited by saline following cocaine pre-exposure closely resembled the 10 mg/kg acute cocaine response. The overall purpose of the second study was to determine if genetic differences in various aspects of such conditioned associations could contribute to individual differences in cocaine dependence. It was determined that, although DBA/2 mice had a faster rate of acquisition of context-dependent sensitization to cocaine than C57/BL6 mice, the multivariate behavior profile of the conditioned response of C57BL/6 mice resembled the behavior observed with a higher dose of acute cocaine and had greater magnitude and greater persistence than that of DBA/2 mice, which may explain in part the susceptibility of the C57BL/6 mice to cocaine dependence.