Mu (mu) opioid receptor regulation of ethanol-induced dopamine response in the ventral striatum: evidence of genotype specific sexual dimorphic epistasis

Biol Psychiatry. 2007 Sep 15;62(6):627-34. doi: 10.1016/j.biopsych.2006.11.016. Epub 2007 Mar 6.

Abstract

Background: Ethanol stimulates the dopaminergic mesoaccumbal pathway, which is thought to play a role in ethanol reinforcement. Mu (mu)-opioid (MOP) receptors modulate accumbal dopamine activity, but it is not clear whether MOP receptors are involved in the mechanism of ethanol-stimulated accumbal dopamine release.

Methods: We investigated the role that MOP receptors play in ethanol (2.0 g/kg)-stimulated accumbal dopamine release by using MOP receptor knockout mice (C57BL/6J-129SvEv and congenic C57BL/6J genotypes) along with blockade of MOP receptors with a mu1 selective antagonist (naloxonazine).

Results: Both gene deletion and pharmacological antagonism of the MOP receptor decreased ethanol-stimulated accumbal dopamine release compared with controls with female mice showing a larger effect in the C57BL/6J-129SvEv genotype. However, both male and female mice showed reduced ethanol-stimulated dopamine release in the congenic MOP receptor knockout mice (C57BL/6J). No differences in the time course of dialysate ethanol concentration were found in any of the experiments.

Conclusions: The data demonstrate the existence of a novel interaction between genotype and sex in the regulation of ethanol-stimulated mesolimbic dopamine release by the MOP receptor. This implies that a more complete understanding of the epistatic influences on the MOP receptor and mesolimbic dopamine function may provide more effective pharmacotherapeutic interventions in the treatment of alcoholism.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / genetics
  • Alcohol Drinking / metabolism
  • Alcohol Drinking / physiopathology
  • Alcoholism / physiopathology
  • Alcoholism / therapy
  • Animals
  • Basal Ganglia / drug effects*
  • Basal Ganglia / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dopamine / physiology
  • Epistasis, Genetic*
  • Ethanol / pharmacology*
  • Genotype
  • Humans
  • Mice
  • Mice, Congenic
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microdialysis
  • Naloxone / analogs & derivatives
  • Naloxone / pharmacology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / genetics
  • Receptors, Opioid, mu / physiology*
  • Reinforcement, Psychology
  • Sex Characteristics*

Substances

  • Receptors, Opioid, mu
  • Naloxone
  • Ethanol
  • naloxonazine
  • Dopamine