Elsevier

Biological Psychiatry

Volume 62, Issue 6, 15 September 2007, Pages 627-634
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2006.11.016Get rights and content

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.

Section snippets

Subjects

Mice (male and female, 4–16 months old, 21–38 g) were obtained from the National Institute on Drug Abuse (NIDA, Baltimore, Maryland) or bred at the University of Texas at Austin. The mice were housed in a humidity and temperature controlled room with a 12:12-hour light/dark cycle (lights on 7 am), and animals had free access to food and water. All animal experiments were conducted under protocols approved by the Institutional Animal Care and Use Committee at the University of Texas, following

Histological Analysis and Ca2+-Dependence of Dopamine Release

The microdialysis probe placements are shown in Figure 1. They were distributed either in the medial NAcc and passed through both the shell and core regions, or exclusively in the shell. The calcium-dependency, a functional measure of the physiological state of the dopamine nerve terminals during microdialysis sampling, was determined for all the animals used in the study. The criterion for acceptable calcium-dependency was the attainment of at least a 40% decrease in dialysate dopamine

Discussion

Our study is the first to report diminished ethanol-stimulated dopamine release in any MOPr knockout model. A secondary finding from the present study is the novel interaction between sex and genotype in the MOPr-dependence of ethanol-stimulated mesolimbic dopamine release. Female, but not male, 129SvEv-C57BL/6J mice were found to require the MOPr for the expression of the neurochemical response to ethanol. Similar results were observed following pharmacological blockade of the mu1 receptor. In

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  • Cited by (0)

    1

    AT is currently affiliated with Lexicon Genetics Inc., The Woodlands, Texas

    2

    IS is currently affiliated with the Department of Psychobiology (IS), Tohoku University Graduate School of Medicine, Sendai, Japan.

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