Chronic nicotine doses down-regulate PDE4 isoforms that are targets of antidepressants in adolescent female rats.
BACKGROUND
Previous data in humans and animal models has suggested connections between anxiety, depression, smoking behavior, and nicotine dependence. The importance of these connections has been confirmed by clinical studies that led to the recent FDA approval of an anti-depressant (Zyban) for use in human smoking cessation programs. Other anti-depressants (such as rolipram) specifically inhibit PDE4 phosphodiesterases.


METHODS
We used DNA microarrays to discover gene expression changes in adolescent female rats following chronic nicotine treatments, and real-time PCR assays to confirm and extend those results.


RESULTS
We found a consistent decrease in the mRNA levels encoded by the Pde4b gene in nucleus accumbens, prefrontal cortex, and hippocampus of adolescent female rats treated with .24 mg/day nicotine, and in prefrontal cortex of adolescent female rats treated with .12 mg/day nicotine. We further show that each of these brain areas produced a different profile of Pde4b isoforms.


CONCLUSIONS
Chronic nicotine treatments produce a dose-dependent down-regulation of Pde4b, which may have an antidepressant effect. This is the first report of a link between nicotine dependence and phosphodiesterase gene expression. Our results also add to the complex interrelationships between smoking and schizophrenia, because mutations in the PDE4B gene are associated with schizophrenia.
Polesskaya
Oksana O
OO
Center for Biomedical Genomics & Informatics, Department of Molecular & Microbiology, George Mason University, Manassas, Virginia 20110, USA.
Smith
Robert F
RF
Fryxell
Karl J
KJ
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014018:Tissue Distribution
D018722:Nicotinic Agonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D009538:Nicotine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human