Transcriptional regulation of L-type calcium channel subtypes Cav1.2 and Cav1.3 by nicotine and their potential role in nicotine sensitization.
BACKGROUND
L-type calcium channel (LTCC) activity in the brain is mediated by 2 subtypes, Ca(v)1.2 and Ca(v)1.3. The individual contributions of these LTCC subtypes to the long-term pharmacological and behavioral effects of nicotine are unknown.


METHODS
Using quantitative in situ hybridization, we examined expression levels of Ca(v)1.2 and Ca(v)1.3 in forebrain regions of mice treated with nicotine (0.175 mg/kg) or saline for 1 or 14 days and sacrificed 24 hr or 7 days following the last injection. Additionally, we treated mice with nicotine for 14 days and then administered the nonspecific LTCC antagonist nifedipine twice daily during a 7-day abstinence period prior to testing for nicotine sensitization to determine the effect of LTCC blockade on sensitization.


RESULTS
Ca(v)1.2 mRNA was unaffected 24 hr following a single nicotine exposure, whereas Ca(v)1.3 mRNA was upregulated in several brain regions. Following 14 days of nicotine treatment and 24 hr of abstinence, Ca(v)1.2 mRNA was downregulated throughout the areas examined, whereas Ca(v)1.3 mRNA had mostly returned to control values. Following 7 days of abstinence, a strong upregulation of Ca(v)1.2 transcripts was observed, whereas Ca(v)1.3 mRNA was largely unaffected. In our sensitization study, nifedipine administered during nicotine abstinence impaired subsequent nicotine sensitization.


CONCLUSIONS
Our data suggest a differential involvement of Ca(v)1.2 and Ca(v)1.3 in nicotine-related processes. Ca(v)1.3 seems to be involved primarily during early exposure to nicotine. Ca(v)1.2 appears to play a role in the long-term molecular and behavioral changes that occur following chronic nicotine and abstinence. Nifedipine may counteract those nicotine-induced alterations in LTCC activity to impair nicotine sensitization.
Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim /University of Heidelberg, Mannheim, Germany.
Rick E
RE
Bernardi
Stefanie
S
Uhrig
Rainer
R
Spanagel
Anita C
AC
Hansson
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D016548:Prosencephalon / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
C514350:CACNA1C protein, mouse; C485995:Cacna1d protein, mouse; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009538:Nicotine; D009543:Nifedipine