title: Differential Roles for L-Type Calcium Channel Subtypes in Alcohol Dependence.
abstract: It has previously been shown that the 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 naive 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 measured alcohol self-administration and cue-induced reinstatement of alcohol seeking in dependent and nondependent rats after intracerebroventricular (i.c.v.) injection of the LTCC antagonist verapamil, as well as in mice with an inducible knockout (KO) of Cav1.2 in Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα)-expressing neurons. Our results show that Cacna1c mRNA concentration was 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 concentration 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. The inhibition of central LTCCs via i.c.v. administration of verapamil prevented cue-induced reinstatement of alcohol seeking in alcohol-dependent rats. Further studies in conditional Cav1.2-KO mice showed a lack of dependence-induced increase of alcohol-seeking behavior. 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 antirelapse medications.
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Uhrig
authors.affiliation: Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, NIS Center, CNISM, University of Torino, Torino, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Vandael
authors.affiliation: Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, NIS Center, CNISM, University of Torino, Torino, Italy.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0001-5825-7827
authors.initials: A
authors.lastname: Marcantoni
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Dedic
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Bilbao
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Vogt
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Hirth
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Broccoli
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Rick E
authors.initials: RE
authors.lastname: Bernardi
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Schönig
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gass
authors.affiliation: Department of Molecular Biology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Dusan
authors.initials: D
authors.lastname: Bartsch
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Spanagel
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|Department of Addictive Behavior and Addiction Medicine, Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Wolfgang H
authors.identifier: http://orcid.org/0000-0002-5903-6521
authors.initials: WH
authors.lastname: Sommer
authors.affiliation: Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, NIS Center, CNISM, University of Torino, Torino, Italy.
authors.forename: Emilio
authors.identifier: http://orcid.org/0000-0003-2239-6280
authors.initials: E
authors.lastname: Carbone
authors.affiliation: Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
mesh_terms: D000437:Alcoholism / Q000378:metabolism / Q000503:physiopathology*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology*; D058999:Drug-Seeking Behavior; D000431:Ethanol / Q000008:administration & dosage*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger; D017208:Rats, Wistar; D014700:Verapamil / Q000008:administration & dosage
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D012333:RNA, Messenger; C093712:Cacna1d protein, rat; D000431:Ethanol; D014700:Verapamil