Mu (mu) opioid receptor regulation of ethanol-induced dopamine response in the ventral striatum: evidence of genotype specific sexual dimorphic epistasis.
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.
Job
Martin O
MO
Division of Pharmacology, College of Pharmacy, University of Texas, 1 University Station, Austin, TX 78712, USA.
Tang
Amanda
A
Hall
F Scott
FS
Sora
Ichiro
I
Uhl
George R
GR
Bergeson
Susan E
SE
Gonzales
Rueben A
RA
D000428:Alcohol Drinking / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000437:Alcoholism / Q000503:physiopathology / Q000628:therapy; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism* / Q000502:physiology; D004843:Epistasis, Genetic; D000431:Ethanol / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009270:Naloxone / Q000031:analogs & derivatives / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012054:Reinforcement, Psychology; D012727:Sex Characteristics
D017450:Receptors, Opioid, mu; D009270:Naloxone; D000431:Ethanol; C034643:naloxonazine; D004298:Dopamine