Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

  title={Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement},
  author={James R. Shoblock and Natalie Welty and Leah Aluisio and Ian C. Fraser and S. Timothy Motley and Kirsten L. Morton and J Palmer and Pascal Bonaventure and Nicholas I. Carruthers and Timothy W. Lovenberg and Jamin D. Boggs and Ruggero Galici},
RationaleOrexin-1 receptor antagonists have been shown to block the reinforcing effects of drugs of abuse and food. However, whether blockade of orexin-2 receptor has similar effects has not been determined. We have recently described the in vitro and in vivo effects of JNJ-10397049, a selective and brain penetrant orexin-2 receptor antagonist.ObjectiveThe goal of these studies was to evaluate whether systemic administration of JNJ-10397049 blocks the rewarding effects of ethanol and reverses… 

Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models

Results contribute to a growing body of evidence indicating that OX1 and OX2 receptor activity influences ethanol self-administration, although the effects may not be selective for ethanol consumption.

Influence of sigma-1 receptor modulators on ethanol-induced conditioned place preference in the extinction–reinstatement model

It is concluded that sigma-1 receptor ligands can modulate the acquisition, expression, and reinstatement of conditioned reinforcing effects of ethanol with no reinforcing or aversive influence of their own.

Central orexin (hypocretin) 2 receptor antagonism reduces ethanol self-administration, but not cue-conditioned ethanol-seeking, in ethanol-preferring rats.

Findings implicate OX(2)R in the NAc in the nucleus accumbens in mediating the reinforcing effects of ethanol and suggest a potential therapeutic target for the treatment of ethanol-use disorders.

The Dual Orexin/Hypocretin Receptor Antagonist, Almorexant, in the Ventral Tegmental Area Attenuates Ethanol Self-Administration

It is demonstrated that orexin/hypocretin receptors in distinct brain regions regulate ethanol and sucrose mediated behaviors and almorexant decreased operant self-administration of both 20% ethanol and 5% sucrose.



Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long–Evans rats

It is suggested that inhibition of OX-1/Hcrt-1 receptors modulates operant ethanol self-administration and also plays a significant role in yohimbine-induced reinstatement of both ethanol and sucrose seeking in rats.

Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat

Results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system.

Direct Involvement of Orexinergic Systems in the Activation of the Mesolimbic Dopamine Pathway and Related Behaviors Induced by Morphine

Findings provide new evidence that orexin-containing neurons in the VTA are directly implicated in the rewarding effect and hyperlocomotion induced by morphine through activation of the mesolimbic dopamine pathway in rodents.

The hypocretin–orexin system regulates cocaine self‐administration via actions on the mesolimbic dopamine system

These studies suggest that hypocretin neurotransmission participates in reinforcement processes, likely through modulation of the mesolimbic dopamine system, and suggest that the hypoc retin system may provide a target for pharmacotherapies to treat cocaine addiction.

Orexin A/Hypocretin-1 Selectively Promotes Motivation for Positive Reinforcers

Evidence is shown that orexin/hypocretin receptor-1 (ox/hcrt-1R) signaling is important for motivation for highly salient, positive reinforcement and may represent a unique opportunity to design novel therapies that selectively reduce excessive drive to consume positive reinforcers of high salience.

Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior.

  • B. BoutrelP. Kenny L. de Lecea
  • Biology, Psychology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2005
It is shown that intracerebroventricular infusions of Hcrt-1 lead to a dose-related reinstatement of cocaine seeking without altering cocaine intake in rats, and a previously unidentified role for hypocretins in driving drug seeking through activation of stress pathways in the brain is revealed.

The orexin system regulates alcohol‐seeking in rats

Re‐exposure of cues previously associated with alcohol availability is sufficient and adequate to activate orexin‐containing neurons and drive reinstatement of alcohol‐seeking in alcohol‐preferring rats.

Nicotine up-regulates expression of orexin and its receptors in rat brain.

It is demonstrated that an inverse association between nicotine and food intake as well as body weight held with doses comparable to those consumed by average human smokers.

Haloperidol does not alter expression of ethanol-induced conditioned place preference