It has been shown that inhibition of L-type calcium channels (LTCCs) decreases alcohol consumption, although the contribution of the central LTCC subtypes Cav1.2 and Cav1.3 remains unknown. Here, we determined changes in Cav1.2 (Cacna1c) and Cav1.3 (Cacna1d) mRNA and protein expression in alcohol dependent rats during protracted abstinence and in naïve controls using in situ hybridization and Western Blot analysis. Functional validation was obtained by electrophysiological recordings of calcium currents in dissociated hippocampal pyramidal neurons. We then investigated the effect of the centrally applied LTCC antagonist verapamil on alcohol self-administration and cue-induced reinstatement of alcohol-seeking in dependent and non-dependent rats. Our results show that Cacna1c mRNA levels were increased in the amygdala and hippocampus of alcohol dependent rats after 21 days of abstinence, with no changes in Cacna1d mRNA. This was associated with increased Cav1.2 protein levels and L-type calcium current amplitudes. Further analysis of Cacna1c mRNA in the CA1, basolateral amygdala (BLA) and central amygdala (CeA) revealed a dynamic regulation over time during the development of alcohol dependence. Inhibition of central LTCCs through intracerebroventricular (i.c.v.) injection of verapamil did not affect alcohol self-administration behavior, but prevented cue-induced reinstatement of alcohol-seeking in alcohol dependent rats. Together, our data indicate that central Cav1.2 channels, rather than Cav1.3, mediate alcohol-seeking behavior. This finding may be of interest for the development of new anti-relapse medications.

Differential Roles for L-Type Calcium Channel Subtypes in Alcohol Dependence

VANDAEL, DAVID HENRI FRANCOIS;MARCANTONI, Andrea;CARBONE, Emilio;
2017

Abstract

It has been shown that inhibition of L-type calcium channels (LTCCs) decreases alcohol consumption, although the contribution of the central LTCC subtypes Cav1.2 and Cav1.3 remains unknown. Here, we determined changes in Cav1.2 (Cacna1c) and Cav1.3 (Cacna1d) mRNA and protein expression in alcohol dependent rats during protracted abstinence and in naïve controls using in situ hybridization and Western Blot analysis. Functional validation was obtained by electrophysiological recordings of calcium currents in dissociated hippocampal pyramidal neurons. We then investigated the effect of the centrally applied LTCC antagonist verapamil on alcohol self-administration and cue-induced reinstatement of alcohol-seeking in dependent and non-dependent rats. Our results show that Cacna1c mRNA levels were increased in the amygdala and hippocampus of alcohol dependent rats after 21 days of abstinence, with no changes in Cacna1d mRNA. This was associated with increased Cav1.2 protein levels and L-type calcium current amplitudes. Further analysis of Cacna1c mRNA in the CA1, basolateral amygdala (BLA) and central amygdala (CeA) revealed a dynamic regulation over time during the development of alcohol dependence. Inhibition of central LTCCs through intracerebroventricular (i.c.v.) injection of verapamil did not affect alcohol self-administration behavior, but prevented cue-induced reinstatement of alcohol-seeking in alcohol dependent rats. Together, our data indicate that central Cav1.2 channels, rather than Cav1.3, mediate alcohol-seeking behavior. This finding may be of interest for the development of new anti-relapse medications.
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http://www.nature.com/npp/index.html
Pharmacology; Psychiatry and Mental Health
Uhrig, Stefanie; Vandael, David; Marcantoni, Andrea; Dedic, Nina; Bilbao, Ainhoa; Vogt, Miriam A.; Hirth, Natalie; Broccoli, Laura; Bernardi, Rick E.; Schönig, Kai; Gass, Peter; Bartsch, Dusan; Spanagel, Rainer; Deussing, Jan M.; Sommer, Wolfgang H.; Carbone, Emilio; Hansson, Anita C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1633682
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