title: The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration.
abstract: Recent studies have implicated the hypocretin/orexinergic system in reward-seeking behavior. Almorexant, a dual orexin/hypocretin R(1) and R(2) 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 self-administration of both 20% ethanol and 5% sucrose. We further demonstrate that intra-ventral 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.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California, United States of America.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Srinivasan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Simms
authors.forename: Carsten K
authors.initials: CK
authors.lastname: Nielsen
authors.forename: Steven P
authors.initials: SP
authors.lastname: Lieske
authors.forename: Jade J
authors.initials: JJ
authors.lastname: Bito-Onon
authors.forename: Henry
authors.initials: H
authors.lastname: Yi
authors.forename: Frederic Woodward
authors.initials: FW
authors.lastname: Hopf
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.forename: Selena E
authors.initials: SE
authors.lastname: Bartlett
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D000431:Ethanol / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D064446:Orexin Receptors; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013395:Sucrose / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000081:Acetamides; D007546:Isoquinolines; D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D000431:Ethanol; D013395:Sucrose; C519150:almorexant