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dc.contributor.advisorAndrew R. Tapper, Ph.D.
dc.contributor.authorHendrickson, Linzy M
dc.date2022-08-11T08:08:43.000
dc.date.accessioned2022-08-23T16:05:25Z
dc.date.available2022-08-23T16:05:25Z
dc.date.issued2011-01-28
dc.date.submitted2011-05-26
dc.identifier.doi10.13028/174w-zb21
dc.identifier.urihttp://hdl.handle.net/20.500.14038/31864
dc.description.abstractWhile it is clear that most drugs of abuse act to increase extracellular dopamine levels in the nucleus accumbens (NAc), the molecular mechanisms mediating this process vary depending on the molecular target each drug acts on. The rewarding properties of most drugs of abuse including cocaine, amphetamine, and heroin have been well established for some time; however, the molecular mechanisms by which ethanol acts to mediate reward have not been fully elucidated. In this thesis, I have examined the role of nicotinic acetylcholine receptors (nAChRs), known molecular targets for nicotine addiction, in mediating the initial rewarding properties of alcohol. Using a mouse model of voluntary ethanol consumption called Drinking in the Dark (DID), in combination with nAChR pharmacology and mouse genetics, we have provided further evidence for the role of nAChRs in mediating the initial rewarding properties of ethanol. Because of the vast number of possible functional nAChR subtypes present in the brain, I sought to investigate which subtype of nAChR may be responsible for ethanol reinforcement. To accomplish this, I used two complementary nAChR mouse models. The first is a knock-out line that does not express the α4 subunit (α4 KO) and the second is a knock-in line that expresses α4* nAChRs that are hypersensitive to agonist (Leu9′Ala). We have also shown, for the first time, that a specific nAChR subtype, those that contain the α4 subunit (α4*), mediate voluntary ethanol consumption and reward. Next, I examined the role of α4* nAChRs in modulating voluntary ethanol consumption after systemic administration of the FDA approved smoking cessation drug varenicline, a partial agonist of α4* nAChRs. We showed that varenicline and nicotine both reduced acute ethanol consumption in an α4* nAChR dependent mechanism. Taken together, our data indicate that activation of α4* nAChRs is necessary and sufficient for reduction of ethanol consumption and further supports the hypothesis that α4* nAChRs are molecular targets for alcohol cessation therapies.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectReceptors
dc.subjectNicotinic
dc.subjectAcetylcholine
dc.subjectAlcoholic Intoxication
dc.subjectAlcoholism
dc.subjectEthanol
dc.subjectEthanol
dc.subjectMice
dc.subjectInbred
dc.subjectReward
dc.subjectMental Disorders
dc.subjectNervous System
dc.subjectNeuroscience and Neurobiology
dc.subjectOrganic Chemicals
dc.subjectTherapeutics
dc.titleNeuronal Nicotinic Acetylcholine Receptors: Molecular Targets for Alcoholism and Ethanol Reward: A Dissertation
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1528&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/526
dc.legacy.embargo2012-04-19T00:00:00-07:00
dc.identifier.contextkey2034647
refterms.dateFOA2022-08-30T15:17:48Z
html.description.abstract<p>While it is clear that most drugs of abuse act to increase extracellular dopamine levels in the nucleus accumbens (NAc), the molecular mechanisms mediating this process vary depending on the molecular target each drug acts on. The rewarding properties of most drugs of abuse including cocaine, amphetamine, and heroin have been well established for some time; however, the molecular mechanisms by which ethanol acts to mediate reward have not been fully elucidated. In this thesis, I have examined the role of nicotinic acetylcholine receptors (nAChRs), known molecular targets for nicotine addiction, in mediating the initial rewarding properties of alcohol. Using a mouse model of voluntary ethanol consumption called Drinking in the Dark (DID), in combination with nAChR pharmacology and mouse genetics, we have provided further evidence for the role of nAChRs in mediating the initial rewarding<br />properties of ethanol. Because of the vast number of possible functional nAChR subtypes present in the brain, I sought to investigate which subtype of nAChR may be responsible for ethanol reinforcement. To accomplish this, I used two<br />complementary nAChR mouse models. The first is a knock-out line that does not express the α4 subunit (α4 KO) and the second is a knock-in line that expresses α4* nAChRs that are hypersensitive to agonist (Leu9′Ala). We have also shown, for the first time, that a specific nAChR subtype, those that contain the α4 subunit (α4*), mediate voluntary ethanol consumption and reward. Next, I examined the role of α4* nAChRs in modulating voluntary ethanol consumption after systemic administration of the FDA approved smoking cessation drug varenicline, a partial agonist of α4* nAChRs. We showed that varenicline and nicotine both reduced acute ethanol consumption in an α4* nAChR dependent mechanism. Taken together, our data indicate that activation of α4* nAChRs is necessary and sufficient for reduction of ethanol consumption and further supports the hypothesis that α4* nAChRs are molecular targets for alcohol cessation therapies.</p>
dc.identifier.submissionpathgsbs_diss/526
dc.contributor.departmentTapper Lab
dc.contributor.departmentNeurobiology
dc.description.thesisprogramNeuroscience


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