| First Author | Flores Á | Year | 2014 |
| Journal | Biol Psychiatry | Volume | 75 |
| Issue | 6 | Pages | 499-507 |
| PubMed ID | 23896204 | Mgi Jnum | J:283299 |
| Mgi Id | MGI:6386088 | Doi | 10.1016/j.biopsych.2013.06.012 |
| Citation | Flores A, et al. (2014) The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward. Biol Psychiatry 75(6):499-507 |
| abstractText | 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/DeltaFosB 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/DeltaFosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by Delta(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. |
