EXPRESSION OF COCAINE SENSITIZATION - REGULATION BY THE MEDIAL PREFRONTAL CORTEX

Extracellular levels of dopamine are increased in response to systemic administration of cocaine in several brain areas including the nucleu s accumbens and medial prefrontal cortex. While the cocaine-induced in crease in extracellular dopamine levels in the nucleus accumbens is au gmented after repeated daily cocaine, the response of extracellular do pamine levels in the medial prefrontal cortex is attenuated. Since dop amine in the medial prefrontal cortex has an inhibitory effect on nucl eus accumbens dopamine levels and locomotor activity, the role of medi al prefrontal cortex dopamine tolerance in the expression of sensitize d locomotor behavior was further examined by injection of D-amphetamin e sulfate into the prelimbic portion of the medial prefrontal cortex j ust prior to cocaine challenge in cocaine-sensitized rats. Male Spragu e-Dawley rats were non-handled (naive) or injected with either saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) for five consecutive days. After a seven to 12 day withdrawal period, rats were microinjected wi th either saline or various doses of amphetamine into primarily the pr elimbic region of the medial prefrontal cortex follow ed by systemic i njection of saline or cocaine. In naive rats, intramedial prefrontal c ortex amphetamine produced a trend toward decreased locomotor respondi ng to cocaine challenge while no effect of amphetamine was evident in daily saline pretreated rats. Daily cocaine pretreated rats that recei ved saline in the medial prefrontal cortex demonstrated a sensitized l ocomotor response compared to their daily saline pretreated counterpar ts. This sensitization was blocked by a low dose of amphetamine (0.175 mu g/side) in the medial prefrontal cortex, an effect which disappear ed in animals administered higher amphetamine doses. The results sugge st that in rats sensitized to cocaine, decreased medial prefrontal cor tex dopamine levels in response to cocaine challenge may contribute to behavioral sensitization. Furthermore, the data indicate the possibil ity that there is an optimal range at which medial prefrontal cortex a mphetamine exerts maximal behavioral inhibition. These findings implic ate a role for decreased cortical control in producing sensitized beha vioral responding to cocaine. (C) 1998 IBRO. Published by Elsevier Sci ence Ltd.