The Hypocretin/Orexin Receptor-1 as a Novel Target to Modulate Cannabinoid Reward

Background: Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacologic treatment is available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction, but the potential participation of this system in the addictive properties of cannabinoids is unknown. Methods: We investigated the effects of hypocretins in the intravenous self-administration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 antagonists and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double-label immunofluorescence of FosB/Delta FosB with hypocretin-1. Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute Delta(9)-tetrahydrocannabinol administration. Results: Systemic administration of the Hcrtr-1 antagonist SB334867 reduced intravenous self-administration of WIN55,212-2, as well as the maximum effort to obtain a WIN55,212-2 infusion, as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not noncontingent, WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/.FosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by.9-tetrahydrocannabinol was blocked in mice lacking the Hcrtr-1. Conclusions: These findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest.