Cw. Bradberry et al., Rapid induction of behavioral and neurochemical tolerance to cocaethylene,a model compound for agonist therapy of cocaine dependence, PSYCHOPHAR, 146(1), 1999, pp. 87-92
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.