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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 parallel to alpha (CaMKII alpha)-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.
