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Memorial University - Electronic Theses and Dissertations 5
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Document Description
TitleA behavioral investigation of L-type Ca²+ channel subtypes Cav 1.2 and Cav 1.3 in Nicotine addiction
AuthorHarding, Meghan L. (Meghan Lucy), 1985-
DescriptionThesis (M.Sc.)--Memorial University of Newfoundland, 2011. Medicine
Paginationxi, 103 leaves : ill.
SubjectNicotine--Receptors--Effect of drugs on; Nicotine addiction--Psychological aspects; Nicotine addiction--Physiological effect; Cigarette smokers--Psychological aspects; Tobacco--Receptors--Effect of drugs on; Tobacco--Physiological effect; Tobacco--Psychological aspects; Mice as laboratory animals--Effect of drugs on
Subject.MESHNicotine; Nicotine--adverse effects; Tobacco Use Disorder; Mice
Degree GrantorMemorial University of Newfoundland. Faculty of Medicine
NotesBibliography: leaves 91-103.
AbstractNicotine has become one of the most addictive and devastating drugs in recent history. Not only has chronic nicotine use, by way of smoking, been linked to cardiovascular problems, cancer and lung diseases from bronchitis to lung cancer, but it kills 40, 000 Canadians every year. The mesolimbic dopaminergic pathway has been primarily associated with addiction: cells in the ventral tegmental area release dopamine in the nucleus accumbens, which leads to memory and addiction formation. Previously, our lab investigated what initiates burst firing of ventral tegmental area dopamine neurons when cholinergic nicotinic receptors are activated, as burst firing leads to a higher release probability than spike firing. L-type calcium channels have been shown to be crucial in ventral tegmental area dopamine cell burst firing induced by cholinergic activation. While in vitro work in our lab undoubtedly indicates L-type calcium channels mediate burst firing of dopamine cells, the question of whether they also mediate nicotinic activation of the central dopamine system in behaving animals remains open. -- Nicotine is known to decrease anxiety in chronic smokers and is generally followed by anxiogenic side effects upon sudden nicotine cessation, as seen most often with smokers quitting. In order to test what role L-type calcium channels have in nicotine addiction, two transgenic mice models were tested, one lacking the L-type calcium channel subtype Cav1.3 (Cav1.3-/-) and the other having a mutated DHP site in the Cav1.2 alpha subunit (Cav1.2DHP-/-). We tested Cav1.2DHP-/- mice in the elevated plus maze to examine how L-type calcium channels affect anxiety levels following nicotine treatment and blockade of the Cav1.3 subtype. The conditional place preference test allowed us to investigate the addictive properties of nicotine in the two transgenic mouse models and how L-type calcium channel antagonists (nifedipine) would affect them. -- The elevated plus maze revealed that Cav1.2DHP-/- had different baseline anxiety levels compared to wildtype mice. Nicotine was anxiolytic acutely (following one day of treatment) in Cav1.2DHP-/- mice, while in wildtype mice repeated nicotine was seen to induce anxiolytic effects. Upon the application of nifedipine, an L-type calcium channel DHP antagonist (which mechanism of action only is able to block Cav1.3 due to Cav1.2 mice being DHP insensitive), wildtype mice showed a further decrease in anxiety, while Cav1.2DHP-/- showed no change, indicating that Cav1.3 subtype may play a lesser role in anxiety than Cav1.2. -- Wildtype and Cav1.2DHP-/- mice showed a strong nicotine place preference (time spent in the drug conditioned arm over the neutral arm) of approximately 100 seconds. Nifedipine pretreatment in Cav1.2DHP-/- and wildtype (which blocked both Cav1.2 and Cav1.3) mice abolished the conditional preference for nicotine, suggesting Cav1.3 mediated nicotinic preference. However, when Cav1.3-/- mice were tested for nicotine preference, their conditioned place preference was similar to that in wildtype and Cav1.2DHP-/- mice. Further work is needed to understand the differential involvement of these subtypes in nicotine-induced place conditioning. -- In conclusion our results indicate that the L-type calcium channel subtype Cav1.2 may be more actively involved in anxiety, while Cav1.3, when present, appears to be more critical in inducing nicotine preference. Failure to confirm this finding in Cav1.3-/- mice may be due to compensatory changes in other L-type subtypes or redundant reward circuitry.
Resource TypeElectronic thesis or dissertation
FormatImage/jpeg; Application/pdf
SourcePaper copy kept in the Centre for Newfoundland Studies, Memorial University Libraries
RightsThe author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
CollectionElectronic Theses and Dissertations
Scanning StatusCompleted
PDF File(12.37 MB) --
CONTENTdm file name14390.cpd