Kappa agonist-induced reinstatement of cocaine seeking in squirrel monkeys: a role for opioid and stress-related mechanisms.

Kappa opioid agonists were at one time proposed as candidate pharmacotherapies for cocaine addiction, mainly because of their ability to decrease dopamine neurotransmission and attenuate the behavioral effects of cocaine in laboratory animals. Recent studies, however, suggest that kappa agonists also may mimic and/or enhance some of the effects of cocaine through mechanisms related to stress. The current study used a reinstatement procedure to examine the ability of the kappa agonists spiradoline and enadoline to reinstate extinguished cocaine seeking in squirrel monkeys previously trained to self-administer cocaine under a second-order schedule of i.v. drug injection. Opioid- and stress-related mechanisms were evaluated in antagonism studies with the opioid antagonists naltrexone and nor-binaltorphimine (nor-BNI), the corticotropin-releasing factor receptor antagonist butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP 154,526), and the alpha(2)-adrenoceptor agonist clonidine combined with either spiradoline or enadoline. When tested alone, priming with spiradoline and enadoline induced significant reinstatement of cocaine-seeking behavior to approximately 45% of the maximum reinstatement induced by cocaine. Reinstatement of cocaine seeking induced by intermediate doses of spiradoline was greater in the presence than in the absence of response-contingent presentations of a cocaine-paired stimulus. Spiradoline- and enadoline-induced reinstatement of drug seeking was attenuated by naltrexone but not by nor-BNI. Spiradoline-induced reinstatement of cocaine seeking was also antagonized by CP 154,526 and clonidine. The results point to interactions between a subpopulation of kappa opioid receptors and central corticotropin-releasing factor and noradrenergic stress systems in the reinstatement of cocaine seeking induced by kappa agonists.