title: Greater ethanol inhibition of presynaptic dopamine release in C57BL/6J than DBA/2J mice: Role of nicotinic acetylcholine receptors.
abstract: The mesolimbic dopamine system, originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc), has been heavily implicated in the reinforcing effects of ethanol. Recent slice voltammetry studies have shown that ethanol inhibits dopamine release selectively during high-frequency activity that elicits phasic dopamine release shown to be important for learning and reinforcement. Presently, we examined ethanol inhibition of electrically evoked NAc dopamine in two mouse strains with divergent dopamine responses to ethanol, C57BL/6 (C57) and DBA/2J (DBA) mice. Previous electrophysiology and microdialysis studies have demonstrated greater ethanol-induced VTA dopaminergic firing and NAc dopamine elevations in DBA compared to C57 mice. Additionally, DBA mice have greater ethanol responses in dopamine-related behaviors, including hyperlocomotion and conditioned place preference. Currently, we demonstrate greater sensitivity of ethanol inhibition of NAc dopamine signaling in C57 compared to DBA mice. The reduced sensitivity to ethanol inhibition in DBA mice may contribute to the overall greater ethanol-induced dopamine signaling and related behaviors observed in this strain. NAc cholinergic activity is known to potently modulate terminal dopamine release. Additionally, ethanol is known to interact with multiple aspects of nicotinic acetylcholine receptor activity. Therefore, we examined ethanol-mediated inhibition of dopamine release at two ethanol concentrations (80 and 160 mM) during bath application of the non-selective nicotinic receptor antagonist mecamylamine, as well as compounds selective for the β2-(dihydro-β-erythroidine hydrobromide; DhβE) and α6-(α-conotoxin MII [H9A; L15A]) subunit-containing receptors. Mecamylamine and DhβE decreased dopamine release and reduced ethanol's inhibitory effects on dopamine in both DBA and C57 mice. Further, α-conotoxin also reduced the dopamine release and the dopamine-inhibiting effects of ethanol at the 80 mM, but not 160 mM, concentration. These data suggest that ethanol is acting in part through nicotinic acetylcholine receptors, or downstream effectors, to reduce dopamine release during high-frequency activity.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157, United States.
authors.forename: J T
authors.initials: JT
authors.lastname: Yorgason
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157, United States.
authors.forename: J H
authors.initials: JH
authors.lastname: Rose
authors.affiliation: George E. Wahlen Veterans Affairs Medical Center and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT 84108, United States.
authors.forename: J M
authors.initials: JM
authors.lastname: McIntosh
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157, United States.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ferris
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157, United States. Electronic address: srjones@wakehealth.edu.
authors.forename: S R
authors.initials: SR
authors.lastname: Jones
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018733:Nicotinic Antagonists / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013045:Species Specificity; D046509:Tissue Culture Techniques
chemical_list: D002492:Central Nervous System Depressants; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D000431:Ethanol; D008464:Mecamylamine; D004298:Dopamine
keywords: C57BL/6 DBA/2 mice; ethanol vulnerability; mecamylamine; nucleus accumbens; phasic dopamine; voltammetry