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dc.contributor.authorLiu, Liwang
dc.contributor.authorHendrickson, Linzy M.
dc.contributor.authorGuildford, Melissa
dc.contributor.authorZhao-Shea, Rubing
dc.contributor.authorGardner, Paul D.
dc.contributor.authorTapper, Andrew R.
dc.date2022-08-11T08:08:34.000
dc.date.accessioned2022-08-23T15:59:20Z
dc.date.available2022-08-23T15:59:20Z
dc.date.issued2013-04-15
dc.date.submitted2013-07-02
dc.identifier.citation<p>Biol Psychiatry. 2013 Apr 15;73(8):738-46. doi: 10.1016/j.biopsych.2012.09.019. <a href="http://dx.doi.org/10.1016/j.biopsych.2012.09.019">Link to article on publisher's site</a></p>
dc.identifier.issn0006-3223 (Linking)
dc.identifier.doi10.1016/j.biopsych.2012.09.019
dc.identifier.pmid23141806
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30644
dc.description.abstractBACKGROUND: 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23141806&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttp://dx.doi.org/10.1016/j.biopsych.2012.09.019
dc.subjectReceptors, Nicotinic
dc.subjectDopaminergic Neurons
dc.subjectEthanol
dc.subjectAlcoholism
dc.subjectMental Disorders
dc.subjectMolecular and Cellular Neuroscience
dc.subjectNeuroscience and Neurobiology
dc.subjectSubstance Abuse and Addiction
dc.titleNicotinic acetylcholine receptors containing the alpha4 subunit modulate alcohol reward
dc.typeJournal Article
dc.source.journaltitleBiological psychiatry
dc.source.volume73
dc.source.issue8
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/92
dc.identifier.contextkey4276307
html.description.abstract<p>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.</p> <p>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.</p> <p>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.</p> <p>CONCLUSIONS: Together, these data indicate that nAChRs containing the alpha4 subunit modulate alcohol reward. All rights reserved.</p>
dc.identifier.submissionpathfaculty_pubs/92
dc.contributor.departmentGardner Lab
dc.contributor.departmentTapper Lab
dc.contributor.departmentDepartment of Psychiatry
dc.contributor.departmentBrudnick Neuropsychiatric Research Institute
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.source.pages738-46
dc.contributor.studentMelissa Guildford Derner
dc.contributor.studentLinzy Hendrickson
dc.description.thesisprogramNeuroscience


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