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The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration

Srinivasan, Subhashini, Simms, Jeff, Nielsen, Carsten, Lieske, Steven, Bito-Ono, Jade, Yi, Henry, Hopf, Woody, Bonci, Antonello, & Bartlett, Selena (2012) The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration. PloS ONE, 7(9).

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Abstract

Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R1 and R2 receptor antagonist, has proven effective in preclinical studies in promoting sleep in animal models and was in Phase III clinical trials for sleep disorders. The present study combines behavioral assays with in vitro biochemical and electrophysiological techniques to elucidate the role of almorexant in ethanol and sucrose intake. Using an operant self-administration paradigm, we demonstrate that systemic administration of almorexant decreased operant selfadministration of both 20% ethanol and 5% sucrose. We further demonstrate that intraventral tegmental area (VTA) infusions, but not intra substantia nigra infusions, of almorexant reduced ethanol self-administration. Extracellular recordings performed in VTA neurons revealed that orexin-A increased firing and this enhancement of firing was blocked by almorexant. The results demonstrate that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors.

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11 citations in Scopus
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8 citations in Web of Science®

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ID Code: 53740
Item Type: Journal Article
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Keywords: alcohol, addiction, orexin or hypocretin, ventral tegmental area, electrophysiology
DOI: 10.1371/journal.pone.0044726
ISSN: 1932-6203
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > CLINICAL SCIENCES (110300)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > NEUROSCIENCES (110900)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PHARMACOLOGY AND PHARMACEUTICAL SCIENCES (111500)
Divisions: Current > Schools > School of Clinical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 The authors
Deposited On: 19 Sep 2012 23:36
Last Modified: 01 May 2013 21:02

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