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

Biological Psychiatry Article in Press,
Corrected Proof 6 March 2007

Martin O. Job^a,

Amanda Tang^a,

F. Scott Hall^c,

Ichiro Sora^c,

George R. Uhl^c,

Susan E. Bergeson^b and

Rueben A. Gonzales^a, E-mail: rgonzales@mail.utexas.edu

^aDivision of PharmacologyCollege of Pharmacy
^bthe Waggoner Center for Alcohol and Addiction Research and Sections of Neurobiology and Molecular Genetics and MicrobiologyUniversity of Texas, Austin, Texas
^cMolecular Neurobiology BranchNational Institute on Drug Abuse, Intramural Research Program, National Institute of Health, Baltimore, Maryland; AT is currently affiliated with Lexicon Genetics Inc., The Woodlands, Texas; IS is currently affiliated with the Department of Psychobiology (IS), Tohoku University Graduate School of Medicine, Sendai, Japan

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.

Address reprint requests to Rueben A. Gonzales, Ph.D., University of Texas at Austin, PHAR-Pharmacology, 1 University Station A1915, Austin, Texas 78712-0125