REPEATED COCAINE MODIFIES THE MECHANISM BY WHICH AMPHETAMINE RELEASESDOPAMINE

This study determined whether daily cocaine administration initiates a calcium requirement for the increase in extracellular dopamine produc ed by psychostimulants. The increase in extracellular dopamine induced by perfusion of amphetamine through a microdialysis probe in the nucl eus accumbens shell was enhanced in cocaine-relative to saline-pretrea ted rats. The augmented portion of the amphetamine-induced increase in nucleus accumbens dopamine was abolished by the coperfusion of L- or N-type calcium channel blockers. Inhibition of calcium/calmodulin-depe ndent protein kinase II (CaM-KII) also prevented the augmented increas e in dopamine by amphetamine, whereas inhibition of vesicular exocytos is by botulinum toxin B was ineffective. When the concentration of ext racellular dopamine in the nucleus accumbens was elevated by blocking the plasmallemal dopamine transporter with GBR-12909, the augmented in crease in extracellular dopamine in rats sensitized to repeated cocain e was blocked by a CaM-KII inhibitor. Pretreatment with botulinum toxi n B prevented the increase in extracellular dopamine by GBR-12909 in b oth cocaine-pretreated and control rats. Taken together, these results demonstrate that the psychostimulant-induced enhanced increase in ext racellular dopamine in the nucleus accumbens shell of cocaine-pretreat ed rats arises from the induction of calcium- and CaM-KII-dependent me chanisms.