INCREASED RESPONSIVENESS OF MESOLIMBIC AND MESOSTRIATAL DOPAMINE NEURONS TO COCAINE FOLLOWING REPEATED ADMINISTRATION OF A SELECTIVE KAPPA-OPIOID RECEPTOR AGONIST

Previous data have shown that the repeated administration of kappa-opi oid receptor agonists attenuates the acute behavioral effects of cocai ne. The site and mechanism by which kappa-agonists interact with this psychostimulant, however, are unknown. Accordingly, the present microd ialysis study characterized the effects of prior, repeated administrat ion of the selective kappa-opioid receptor agonist U69593 on basal and cocaine-evoked DA levels within the nucleus accumbens (NAC) and cauda te putamen (CPU). The influence of U69593 treatment on the locomotor-a ctivating effects of an acute cocaine challenge was also assessed. Rat s received once daily injections of U69593 (0.16-0.32 mg/kg/day) or ve hicle (1.0 ml/kg/day) for 3 days. The behavioral and neurochemical eff ects produced by an acute cocaine challenge (20 mg/kg i.p.) were asses sed 2 days following treatment cessation. Administration of cocaine to control animals increased locomotor activity. This effect was attenua ted in animals which had previously received U69593 (0.32 mg/kg/day x 3 days). Prior administration of U69593 failed to modify basal DA leve ls in either the NAC or CPU. Thus, 2 days following the cessation of U 69593 treatment, dialysate DA levels did not differ from that of contr ols. Administration of cocaine to vehicle-treated animals increased di alysate levels of DA in both brain regions. However, in animals previo usly exposed to U69593 (0.32 mg/kg/day x 3 days), a significant enhanc ement in the response of DA neurons to cocaine was seen. These data de monstrate that prior, repeated administration of a selective kappa-opi oid receptor agonist attenuates the locomotor-activating effects of co caine and increases cocaine-evoked DA overflow in terminal projection areas of mesostriatal and mesolimbic DA neurons. These findings indica te that the behavioral interactions of kappa-agonists with cocaine obs erved in this and previous studies cannot be attributed to a presynapt ic inhibition of DA release. Rather, they suggest that postsynaptic or non-DA mechanisms mediate the interaction of these agents with cocain e. Synapse 30:255-262, 1998. (C) 1998 Wiley-Liss, Inc.dagger