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

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• 作者：Á ; frica Flores ; Rafael Maldonado ; Fernando Berrendero ; ^{fernando.berrendero@upf.edu" class="auth_mail}
• 关键词：Cannabinoid ; dopamine ; hypocretin ; knockout ; reward ; WIN55 ; 212-2
• 刊名：Biological Psychiatry
• 出版年：15 March, 2014
• 年：2014
• 卷：75
• 期：6
• 页码：499-507
• 全文大小：923 K

文摘

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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/螖FosB with hypocretin-1. Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute 螖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/螖FosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by 螖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.