Modulation of ethanol drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute
Medical Subject Headings
Acetylcholine; Alcoholic Intoxication; Alcoholism; Ethanol; Mice, Inbred; Receptors, Nicotinic; Dopamine
Life Sciences | Medicine and Health Sciences | Neuroscience and Neurobiology
RATIONALE: Recent reports describe a restricted access ethanol consumption paradigm where C57Bl/6J mice drink until intoxicated. Termed "drinking in the dark" (DID), this paradigm has been used as a model of binge drinking. Although neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in alcohol drinking in rats pre-trained to self-administer ethanol, their role in binge-like ethanol consumption is unknown.
OBJECTIVES: To determine if nAChRs are involved in binge drinking as measured by the DID assay in C57Bl/6J mice.
MATERIALS AND METHODS: Adult male C57Bl/6J mice were injected i.p. with nicotinic receptor antagonists including mecamylamine, hexamethonium, dihydro-beta-erythroidine, and methyllycaconitine. Immediately following injection, mice were presented with 20% ethanol for 2 h in the DID assay to measure ethanol consumption. Nicotinic agonists including cytisine and nicotine were also evaluated. The effects of mecamylamine and nicotine on ethanol-induced dopaminergic neuronal activation in the VTA were evaluated via immunohistochemistry.
RESULTS: Mecamylamine dose dependently reduced ethanol consumption; whereas, the peripheral antagonist hexamethonium had no significant effect. Nicotinic agonists, cytisine and nicotine, reduced ethanol consumption. None of the effective nicotinic receptor drugs reduced sucrose drinking. Mecamylamine blocked ethanol activation of dopaminergic neurons while nicotine alone activated them without additional activation by ethanol.
CONCLUSIONS: Neuronal nAChRs are involved in ethanol consumption in the DID paradigm. The effects of mecamylamine, nicotine, and cytisine on ethanol intake appear to be specific because they do not reduce sucrose drinking. Mecamylamine reduces alcohol consumption by blocking activation of dopaminergic neurons; whereas, nicotinic agonists may activate the same reward pathway as alcohol.
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Citation: Psychopharmacology (Berl). 2009 Jul;204(4):563-72. Epub 2009 Feb 27. Link to article on publisher's site