Mu (μ) Opioid Receptor Regulation of Ethanol-Induced Dopamine Response in the Ventral Striatum: Evidence of Genotype Specific Sexual Dimorphic Epistasis

Job, Martin O.; Tang, Amanda; Hall, F. Scott; Sora, Ichiro; Uhl, George R.; Bergeson, Susan E.; Gonzales, Rueben A.

doi:10.1016/j.biopsych.2006.11.016

« Previous Next »Biological Psychiatry
Volume 62, Issue 6 , Pages 627-634, 15 September 2007

Mu (μ) Opioid Receptor Regulation of Ethanol-Induced Dopamine Response in the Ventral Striatum: Evidence of Genotype Specific Sexual Dimorphic Epistasis

Martin O. Job
- Division of Pharmacology, College of Pharmacy, University of Texas, Austin, Texas.
Amanda Tang
- Division of Pharmacology, College of Pharmacy, University of Texas, Austin, Texas.
- AT is currently affiliated with Lexicon Genetics Inc., The Woodlands, Texas
F. Scott Hall
- Molecular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, Baltimore, Maryland.
Ichiro Sora
- Molecular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, Baltimore, Maryland.
- IS is currently affiliated with the Department of Psychobiology (IS), Tohoku University Graduate School of Medicine, Sendai, Japan.
George R. Uhl
- Molecular Neurobiology Branch, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, Baltimore, Maryland.
Susan E. Bergeson
- Waggoner Center for Alcohol and Addiction Research and Sections of Neurobiology and Molecular Genetics and Microbiology, University of Texas, Austin, Texas.
Rueben A. Gonzales
- Division of Pharmacology, College of Pharmacy, University of Texas, Austin, Texas.
- Address reprint requests to Rueben A. Gonzales, Ph.D., University of Texas at Austin, PHAR-Pharmacology, 1 University Station A1915, Austin, Texas 78712-0125

Received 2 August 2006; received in revised form 13 November 2006; accepted 14 November 2006. published online 09 March 2007.

Background

Ethanol stimulates the dopaminergic mesoaccumbal pathway, which is thought to play a role in ethanol reinforcement. Mu (μ)-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 μ1 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.

Key Words: Dopamine, genotype, knockout mice, microdialysis, nucleus accumbens, sexual dimorphism