Nicotinic acetylcholine receptors containing the alpha4 subunit modulate alcohol reward
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Authors
Liu, LiwangHendrickson, Linzy M.
Guildford, Melissa
Zhao-Shea, Rubing
Gardner, Paul D.
Tapper, Andrew R.
Student Authors
Melissa Guildford DernerLinzy Hendrickson
Academic Program
NeuroscienceUMass Chan Affiliations
Gardner LabTapper Lab
Department of Psychiatry
Brudnick Neuropsychiatric Research Institute
Graduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2013-04-15Keywords
Receptors, NicotinicDopaminergic Neurons
Ethanol
Alcoholism
Mental Disorders
Molecular and Cellular Neuroscience
Neuroscience and Neurobiology
Substance Abuse and Addiction
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Show full item recordAbstract
BACKGROUND: Nicotine and alcohol are the two most co-abused drugs in the world, suggesting a common mechanism of action might underlie their rewarding properties. Although nicotine elicits reward by activating ventral tegmental area dopaminergic (DAergic) neurons via high-affinity neuronal nicotinic acetylcholine receptors (nAChRs), the mechanism by which alcohol activates these neurons is unclear. METHODS: Because most high-affinity nAChRs expressed in ventral tegmental area DAergic neurons contain the alpha4 subunit, we measured ethanol-induced activation of DAergic neurons in midbrain slices from two complementary mouse models, an alpha4 knock-out (KO) mouse line and a knock-in line (Leu9'Ala) expressing alpha4 subunit-containing nAChRs hypersensitive to agonist compared with wild-type (WT). Activation of DAergic neurons by ethanol was analyzed with both biophysical and immunohistochemical approaches in midbrain slices. The ability of alcohol to condition a place preference in each mouse model was also measured. RESULTS: At intoxicating concentrations, ethanol activation of DAergic neurons was significantly reduced in alpha4 KO mice compared with WT. Conversely, in Leu9'Ala mice, DAergic neurons were activated by low ethanol concentrations that did not increase activity of WT neurons. In addition, alcohol potentiated the response to ACh in DAergic neurons, an effect reduced in alpha4 KO mice. Rewarding alcohol doses failed to condition a place preference in alpha4 KO mice, paralleling alcohol effects on DAergic neuron activity, whereas a sub-rewarding alcohol dose was sufficient to condition a place preference in Leu9'Ala mice. CONCLUSIONS: Together, these data indicate that nAChRs containing the alpha4 subunit modulate alcohol reward. All rights reserved.Source
Biol Psychiatry. 2013 Apr 15;73(8):738-46. doi: 10.1016/j.biopsych.2012.09.019. Link to article on publisher's site
DOI
10.1016/j.biopsych.2012.09.019Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30644PubMed ID
23141806Related Resources
ae974a485f413a2113503eed53cd6c53
10.1016/j.biopsych.2012.09.019