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The involvement of central L-type calcium channel subtypes CaV1.2 and CaV1.3 in alcohol dependence and comorbid mental disorders

Uhrig, Stefanie

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Abstract

Alcohol consumption is a broadly accepted part of many cultures around the world. While for some people it is not a problem to control their intake and use alcohol recreationally, others escalate their drinking until it becomes compulsive. Through cycles of excessive drinking and abstinence, alcohol dependence develops. This process is accompanied and supported by adaptations in the brain, including neurotransmitter and hormone systems as well as ion channels. Many of these systems are also altered in nicotine dependence, schizophrenia and depression, in part explaining the high comorbidity between these disorders and alcohol dependence. For the development of new drug therapies, an endeavor necessitated by the lack of efficient medications, it is imperative to understand the underlying mechanisms of each of these disorders. One possible target are the L-type calcium channels (LTCCs), which are influenced by both alcohol and nicotine, and have also been implicated in the risk to develop schizophrenia and depression. However, the two central LTCC subtypes CaV1.2 (Cacna1c) and CaV1.3 (Cacna1d) may play different roles, which have not yet been defined. This thesis aims to identify the individual involvement of CaV1.2 and CaV1.3 in alcohol dependence, and determine whether similar contributions of these subtypes can be found in comorbid disorders.

In Study I, Cacna1c mRNA levels are found to be dynamically regulated during intoxication, withdrawal, and protracted abstinence, with a strong increase in the amygdala and hippocampus after 21 days of abstinence. While Cacna1d mRNA remains unchanged at this time, CaV1.2 protein levels and currents are also increased. Furthermore, antagonism of central LTCCs prevents cue-induced reinstatement of alcohol seeking. Other genetic and functional models of alcohol dependence do not show a clear distinction between Cacna1c and Cacna1d mRNA expression (Study II). Transgenic mice with a CaV1.2 knockout (KO) in Ca2+/calmodulin-dependent protein kinase II (CaMKII)-positive neurons did not show a dependence-induced increase of alcohol intake, which their control littermates displayed clearly (Study III). Similarly to alcohol dependence, Study IV shows increased Cacna1c mRNA after chronic administration of nicotine and subsequent abstinence, while Cacna1d mRNA is increased one day after a single nicotine injection. An augmented nicotine sensitization after abstinence from chronic nicotine was prevented by nifedipine administration during abstinence. Additionally, CaV1.2 KO in CaMKII-positive neurons prevented nicotine self-administration behavior. Study V investigated CACNA1C and CACNA1D mRNA expression in postmortem samples of schizophrenia patients, alcoholics, and suicide completers. In schizophrenia, both subtypes were decreased in the prefrontal and temporal cortex. No changes caused by alcohol dependence or depression were found.

In conclusion, this thesis provides evidence for a crucial role of CaV1.2 in prolonged abstinence from chronic alcohol and nicotine, with effects on drug seeking and craving. It further underlines the importance of central LTCCs in some aspects of schizophrenia. Altogether, it highlights CaV1.2 as promising target for the development of new therapies for drug dependence and comorbid mental disorders.

Item Type: Dissertation
Supervisor: Spanagel, Prof. Dr. Rainer
Date of thesis defense: 8 June 2016
Date Deposited: 14 Jul 2016 09:08
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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