Discrete cue-conditioned alcohol-seeking after protracted abstinence: pattern of neural activation and involvement of orexin₁ receptors

Br J Pharmacol. 2011 Feb;162(4):880-9. doi: 10.1111/j.1476-5381.2010.01088.x.


Background and purpose: The enduring propensity for alcoholics to relapse even following years of abstinence presents a major hurdle for treatment. Here we report a model of relapse following protracted abstinence and investigate the pattern of neuronal activation following cue-induced reinstatement and administration of the orexin₁ receptor antagonist SB-334867 in inbred alcohol-preferring rats.

Experimental approach: Rats were trained to self-administer alcohol under operant conditions and divided into two groups: immediate (reinstated immediately following extinction) and delayed (extinguished and then housed for 5 months before reinstatement). Prior to reinstatement, animals were treated with vehicle (immediate n= 11, delayed n= 11) or SB-334867 (20 mg·kg⁻¹ i.p.; immediate n= 6, delayed n= 11). Fos expression was compared between each group and to animals that underwent extinction only.

Key results: SB-334867 significantly attenuated cue-induced reinstatement in both groups. Immediate reinstatement increased Fos expression in the nucleus accumbens (NAc), infra-limbic (IL), pre-limbic (PrL), orbitofrontal (OFC) and piriform cortices, the lateral and dorsomedial hypothalamus, central amygdala and basolateral amygdala (BLA), and the bed nucleus of the stria terminalis. Following delayed reinstatement, Fos expression was further elevated in cortical structures. Concurrent with preventing reinstatement, SB-334867 decreased Fos in NAc core, PrL and OFC following immediate reinstatement. Following protracted abstinence, SB-334867 treatment decreased reinstatement-induced Fos in the PrL, OFC and piriform cortices.

Conclusions and implications: Cue-induced alcohol seeking can be triggered following protracted abstinence in rats. The effects of SB-334867 on both behaviour and Fos expression suggest that the orexin system is implicated in cue-induced reinstatement, although some loci may shift following protracted abstinence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Deterrents / pharmacology
  • Alcohol Deterrents / therapeutic use
  • Alcohol Drinking*
  • Alcoholism / drug therapy
  • Alcoholism / metabolism*
  • Alcoholism / pathology
  • Animals
  • Behavior, Animal / drug effects*
  • Benzoxazoles / pharmacology
  • Benzoxazoles / therapeutic use
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Conditioning, Operant
  • Cues
  • Male
  • Naphthyridines
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Orexin Receptors
  • Organ Specificity
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Temperance
  • Urea / analogs & derivatives
  • Urea / pharmacology
  • Urea / therapeutic use


  • 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
  • Alcohol Deterrents
  • Benzoxazoles
  • Naphthyridines
  • Nerve Tissue Proteins
  • Orexin Receptors
  • Proto-Oncogene Proteins c-fos
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Urea