Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: comparison with natural reward seeking.

Hypothalamic orexin/hypocretin (Orx/Hcrt) peptides participate in the regulation of a wide range of physiological processes and are recruited by drugs of abuse. To advance our understanding of the potential of the Orx/Hcrt receptor-1 (Hcrt-r1) as a treatment target for cocaine addiction, the effect of SB334867 [N-(2-methyl-6-benzoxazolyl)-N'-1,5-n-aphthyridin-4-yl urea], a specific Hcrt-r1 antagonist, on reinstatement elicited by cocaine-associated stimuli versus stimuli associated with a highly palatable conventional reinforcer [sweetened condensed milk (SCM)] was tested. Two separate groups of male Wistar rats were trained to associate a discriminative stimulus (S⁺) with the response-contingent availability of cocaine (0.25 mg/0.1 ml/infusion) or SCM [2/1 (v/v)] and subjected to reinstatement tests following extinction of cocaine-reinforced or SCM-reinforced behavior, during which the reinforcers and S⁺ were withheld. Following extinction, presentation of the cocaine or SCM S⁺ produced comparable recovery of responding. Hcrt-r1 blockade by SB334867 (1-10 mg/kg, intraperitoneal) dose-dependently and selectively reversed conditioned reinstatement induced by cocaine-related stimuli, without interfering with reward seeking produced by the same stimulus when conditioned to SCM. The findings suggest an important role for Hcrt-r1 in appetitive behavior controlled by reward-related stimuli with selectivity for cocaine seeking and identify Hcrt-r1 as a potential treatment target for cocaine relapse prevention.