Chronic effect of nicotine on serotonin transporter mRNA in the raphe nucleus of rats: Reversal by co‐administration of bupropion

Abstract

Aim: 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.

Serotonin transporter and receptor genes significantly impact nicotine dependence through genetic interactions in both European American and African American smokers

“…Prior studies have reported mixed effects of chronic nicotine exposure on the density of 5-HTTs, thus regulating the amount of synaptic serotonin available for 5-HT 3 receptors. For example, Semba and Wakuta (2008) reported a reduction in the density of 5-HTTs in the rat brain whilst two other studies reported an elevation in 5-HTTs (Awtry and Werling, 2003; Slotkin and Seidler, 2010). On the other hand, Staley et al (2001) reported an elevation 5-HTTs in the human brain, and in human platelets they were reported to be reduced (Patkar et al, 2003).…”

Compromised neuroplasticity in cigarette smokers under nicotine withdrawal is restituted by the nicotinic α4β2-receptor partial agonist varenicline

“…The reason for this discrepancy is unclear, as the groups are similar for age, gender distribution, Fagerstöm scores and withdrawal durations. Possible explanations include inter-group differences of the effects of chronic nicotine exposure on other neuromodulatory systems such as dopamine and serotonin 52, 53 , as well as Brain-derived neurotrophic factor (BDNF) levels 54 , which are shown to have an impact on stimulation-induced plasticity 55–57 . Varenicline administration probably activated α 4 β 2 nAChRs, which are assumed to be desensitized by chronic nicotine exposure 58, 59 , thus facilitating intracellular calcium influx and therefore enabling either LTP or LTD-like after-effects after tDCS and PAS.…”

Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice

“…In addition, many concerns exist about the risks of using a potentially hazardous chemical to treat AD patients (Baldinger and Schroeder, 1995). Similarly, literature surveying the effect of nicotine on depressive-like behavior is ambivalent with some preclinical studies reporting decreased (Djuric et al, 1999; Semba and Wakuta, 2008) or increased (Hayase, 2007, 2008, 2011, 2013) depressive behavior with nicotine use.…”