Dysregulation of nociceptin/orphanin FQ activity in the amygdala is linked to excessive alcohol drinking in the rat

Biol Psychiatry. 2008 Aug 1;64(3):211-8. doi: 10.1016/j.biopsych.2008.02.004. Epub 2008 Mar 25.


Background: Alcoholism is a complex behavioral disorder in which interactions between stressful life events and heritable susceptibility factors contribute to the initiation and progression of disease. Neural substrates of these interactions remain largely unknown. Here, we examined the role of the nociceptin/orphanin FQ (N/OFQ) system, with an animal model in which genetic selection for high alcohol preference has led to co-segregation of elevated behavioral sensitivity to stress (Marchigian Sardinian alcohol-preferring [msP]).

Methods: The msP and Wistar rats trained to self-administer alcohol received central injections of N/OFQ. In situ hybridization and receptor binding assays were also performed to evaluate N/OFQ receptor (NOP) function in naïve msP and Wistar rats.

Results: Intracerebroventricular (ICV) injection of N/OFQ significantly inhibited alcohol self-administration in msP but not in nonselected Wistar rats. The NOP receptor messenger RNA expression and binding was upregulated across most brain regions in msP compared with Wistar rats. However, in msP rats [(35)S]GTPgammaS binding revealed a selective impairment of NOP receptor signaling in the central amygdala (CeA). Ethanol self-administration in msP rats was suppressed after N/OFQ microinjection into the CeA but not into the bed nucleus of the stria terminalis or the basolateral amygdala.

Conclusions: These findings indicate that dysregulation of N/OFQ-NOP receptor signaling in the CeA contributes to excessive alcohol intake in msP rats and that this phenotype can be rescued by local administration of pharmacological doses of exogenous N/OFQ. Data are interpreted on the basis of the anti-corticotropin releasing factor (CRF) actions of N/OFQ and the significance of the CRF system in promoting excessive alcohol drinking in msP rats.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohol Drinking / genetics
  • Alcohol Drinking / pathology*
  • Alcohol Drinking / psychology
  • Amygdala / drug effects
  • Amygdala / metabolism*
  • Analysis of Variance
  • Animals
  • Autoradiography / methods
  • Behavior, Animal
  • Central Nervous System Depressants / administration & dosage*
  • Ethanol / administration & dosage*
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Injections, Intraventricular
  • Motor Activity / drug effects
  • Opioid Peptides / metabolism*
  • Opioid Peptides / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Opioid / genetics
  • Receptors, Opioid / metabolism
  • Reinforcement Schedule
  • Self Administration / psychology
  • Vasodilator Agents / metabolism*
  • Vasodilator Agents / pharmacology


  • Central Nervous System Depressants
  • Opioid Peptides
  • Receptors, Opioid
  • Vasodilator Agents
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Ethanol
  • nociceptin
  • nociceptin receptor