Rapid induction of behavioral and neurochemical tolerance to cocaethylene,a model compound for agonist therapy of cocaine dependence

Rationale: Tolerance to abused drugs may impact on patterns of abuse, and i n the case of agonist therapies, may be beneficial in that it reduces the r eward value of a given dose of abused drug. Cocaethylene, a psychoactive me tabolite resulting from concurrent alcohol and cocaine consumption, was exa mined because of its use in human research studies of drug reward mechanism s, and its potential as a model compound for an agonist based therapy for c ocaine dependence. Objective: Comparisons were made between cocaine and coc aethylene in the acute development of tolerance to the neurochemical and be havioral effects of cocaine. With chronic exposure, tolerance to the behavi oral effects of cocaine was examined. Methods: In awake rats with a microdi alysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3 -h infusion of cocaine or cocaethylene and a subsequent cocaine challenge w as administered while extracellular dopamine and locomotion were monitored. Chronic TV treatment with cocaine, cocaethylene, and a water control was a ccomplished for 7 days using osmotic minipumps attached to jugular catheter s. Animals were then challenged with an IV bolus of cocaine. Results: With acute treatment, the TV bolus of cocaethylene at the beginning of the infus ion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extra cellular concentration of dopamine. However, after that initial increase, l evels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A I-week infusion of cocaine or cocaethylene res ulted in tolerance to the behavioral activating effects of a subsequent coc aine challenge. Conclusions: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both a cutely and after 7 days. The relevance of these data for the use of cocaeth ylene as a model compound for an agonist approach to therapy for cocaine de pendence is discussed.