KAPPA-OPIOID RECEPTOR AGONISTS PREVENT SENSITIZATION TO THE CONDITIONED REWARDING EFFECTS OF COCAINE

A place preference conditioning procedure was used to examine the infl uence of kappa-opioid receptor ligands upon the development of sensiti zation to the conditioned rewarding effects of cocaine. Previous expos ure to cocaine (10-20 mg/kg; i.p.; days 1-5) resulted in an enhancemen t of the conditioned rewarding effects of this agent, e.g., sensitizat ion, Thus, doses of cocaine (5.0-10.0 mg/kg; i.p.) that failed to prod uce place preferences in control rats produced significant place prefe rences in cocaine-experienced animals. In animals that had received th e kappa-agonist U50,488H (5.0 mg/kg; s.c.) in combination with the rep eated cocaine treatment regimen, no enhancement of cocaine-induced pla ce conditioning was seen. Similarly, the kappa-agonist C169593 adminis tered on days 1 to 5 or only on days 3 to 5 of the cocaine treatment r egimen prevented the enhanced response to cocaine. This effect occurre d after either systemic (0.04-0.16 mg/kg; s.c.) or intracerebroventric ular (1.0 mg) treatment and was abolished by the kappa-opioid receptor antagonist, nor-binaltorphimine. In contrast to its effects when admi nistered in combination with cocaine, prior administration of U69593, alone, failed to modify the conditioned response to cocaine. Microdial ysis studies revealed a marked elevation of extracellular dopamine lev els within the ventral striatum after repeated cocaine administration. In animals that had received U69593 in combination with cocaine, no e levation of dopamine was seen. These data demonstrate that sensitizati on develops to the conditioned rewarding effects of cocaine and that t he activation of central nervous system kappa-opioid receptors prevent s the development of this phenomenon, An involvement of the mesolimbic dopamine system in mediating the interaction of kappa-agonists with c ocaine is suggested.