Chronic effect of nicotine on serotonin transporter mRNA in the raphe nucleus of rats: reversal by co-administration of bupropion.
OBJECTIVE
Epidemiologic studies suggest the existence of a biological link between nicotine withdrawal and depression. To investigate the neuronal mechanisms of the precipitation of depression during smoking cessation, an animal model of nicotine withdrawal was used, and the expression of serotonin transporter (5HTT), abnormality of which is implicated in the pathogenesis of depression, was investigated. The effect of co-administration of bupropion, which has been clinically shown to ameliorate nicotine withdrawal symptoms, was also investigated in this model.


METHODS
Male Wistar rats were implanted with a minipump s.c., which delivered nicotine at a rate of 6 mg/kg per day for 12 days (days 1-12). Rats given chronic nicotine were killed on day 13, or 2 days after the removal of minipump (withdrawal day 2). In a separate experiment, bupropion (15 or 30 mg/kg per day) was injected into the nicotine infused rats on days 2-12. The expression of mRNA for 5HTT in the dorsal raphe was determined on in situ hybridization.


RESULTS
Chronic nicotine infusion resulted in the reduction of 5HTT mRNA expression, which lasted through withdrawal day 2. Co-administration of bupropion, however, significantly antagonized this reduction.


CONCLUSIONS
Chronic nicotine infusion reduces the synthesis of 5HTT protein, which may consequently precipitate depression during nicotine withdrawal, but co-administration of bupropion may ameliorate withdrawal symptoms by counteracting nicotine's effect on 5HTT.
Semba
Jun'ichi
J
Division of Health Sciences, The Open University of Japan, Chiba, Japan. sembaj@u-air.ac.jp
Wakuta
Maki
M
D000818:Animals; D016642:Bupropion / Q000494:pharmacology*; D003863:Depression / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009538:Nicotine / Q000494:pharmacology* / Q000633:toxicity; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics*; D011903:Raphe Nuclei / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D016540:Smoking Cessation / Q000523:psychology*; D013375:Substance Withdrawal Syndrome / Q000235:genetics
D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D016642:Bupropion; D009538:Nicotine