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

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.
AuthorsSubhashini Srinivasan, Jeffrey A Simms, Carsten K Nielsen, Steven P Lieske, Jade J Bito-Onon, Henry Yi, Frederic Woodward Hopf, Antonello Bonci, Selena E Bartlett
JournalPloS one (PLoS One) Vol. 7 Issue 9 Pg. e44726 ( 2012) ISSN: 1932-6203 [Electronic] United States
PMID23028593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Acetamides
  • Isoquinolines
  • Orexin Receptors
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Ethanol
  • Sucrose
  • almorexant
  • Acetamides (pharmacology)
  • Animals
  • Electrophysiology
  • Ethanol (metabolism)
  • Isoquinolines (pharmacology)
  • Male
  • Motor Activity (drug effects)
  • Orexin Receptors
  • Rats
  • Receptors, G-Protein-Coupled (antagonists & inhibitors)
  • Receptors, Neuropeptide (antagonists & inhibitors)
  • Sucrose (metabolism)
  • Ventral Tegmental Area (drug effects, metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: