The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward

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• dc.contributor.author Flores de los Heros, África, 1985-ca
• dc.contributor.author Maldonado, Rafael, 1961-ca
• dc.contributor.author Berrendero Díaz, Fernando, 1971-ca
• dc.date.accessioned 2015-03-30T07:21:16Z
• dc.date.available 2015-03-30T07:21:16Z
• dc.date.issued 2014ca
• dc.description.abstract 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/ΔFosB with hypocretin-1. Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute Δ(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/ΔFosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by Δ(9)-tetrahydrocannabinol was blocked in mice lacking the Hcrtr-1. CONCLUSIONS: /nThese findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest.
• dc.description.sponsorship This work was supported by the Instituto de Salud Carlos III grants, #PI07/0559, #PI10/00316 and #RD06/001/001 (RTA-RETICS), by the Spanish Ministry of Science and Technology, Consolider-C #SAF2007-64062 and #SAF2011-29864, the Catalan Government (SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies (ICREA Academia program). África Flores is recipient of a predoctoral fellowship from the Spanish Ministry of Education
• dc.format.mimetype application/pdfca
• dc.identifier.citation Flores Á, Maldonado R Berrendero F. The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid reward. Biol Psychiatry. 2014 Mar 15;75(6):499-507. DOI: 10.1016/j.biopsych.2013.06.012ca
• dc.identifier.doi http://dx.doi.org/10.1016/j.biopsych.2013.06.012
• dc.identifier.issn 0006-3223ca
• dc.identifier.uri http://hdl.handle.net/10230/23308
• dc.language.iso engca
• dc.publisher Elsevierca
• dc.relation.ispartof Biological Psychiatry. 2014 Mar 15;75(6):499-507
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PN/SAF2007-64062
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-29864
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.biopsych.2013.06.012ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Cannabinoides
• dc.title The hypocretin/orexin receptor-1 as a novel target to modulate cannabinoid rewardca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca