Malta Medical Journal Volume 18 Issue 03 October 2006 23 Abstract Previous experiments have shown that chronic subcutaneous administration of nicotine dose-dependently inhibits the acquisition and retention of a spatial task in the Morris water maze and reduces cell genesis in the dentate gyrus (DG) of adult rats. 1 In the present study, the effects of nicotine and buproprion, an atypical antidepressant used in smoking cessation, on dentate gyrus cell genesis and DNA fragmentation were investigated. The results show that nicotine, chronically infused for 21 days, suppressed cell genesis and enhanced DNA fragmentation in the DG, an effect not attenuated by co-administration of buproprion. Introduction The ability of the hippocampal formation, typically in its dentate gyrus (DG) area, to generate new neurons (neurogenesis) throughout the human lifespan 2 may prove beneicial in the treatment of neurological diseases characterised by neuronal cell loss such as Alzheimer’s and Parkinson’s diseases. Increased neurogenesis can be produced by a variety of treatments including an enriched environment 3 , physical activity 4 and antidepressant drugs. 5,6 Neurogenesis has also been speciically implicated in learning tasks that involve the hippocampus. 7,8 Clinical studies have revealed a strong correlation between the incidence of tobacco use and mood disorders. 9 In animal models, nicotine, infused chronically using a procedure similar to the one reported here, was found to have antidepressant properties. 10 Furthermore, nicotine dependence and withdrawal symptoms were ameliorated by buproprion 11,12 , an atypical antidepressant approved for smoking cessation 13-15 , probably Charles Scerri Original Article Effects of chronic buproprion and nicotine administration on cell genesis and DNA fragmentation in adult rat dentate gyrus Charles Scerri BPharm (Hons), PhD Division of Pathology and Neuroscience Univesity of Dundee Medical School Ninewells Hospital, Dundee, Scotland Email: charles.scerri@um.edu.mt Keywords Nicotine, buproprion, bromodeoxyuridine, DNA fragmentation, hippocampus. via a mechanism involving the inhibition of nicotinic acetylcholine receptors (nAChRs). 16 In vitro studies revealed that buproprion exhibited some selectivity for neuronal nicotinic receptors that comprise a 3 β 2 , a 4 β 2 and a 7 subunits. Inhibition of radioactive nicotine binding to these receptor subtypes by buproprion suggested that the interaction was competitive and contributed to buproprion’s eficacy in counteracting nicotine dependence. 17 It is widely reported that nicotine produces a protective effect against induced apoptosis 18-21 in which one of the hallmarks is DNA fragmentation. Nevertheless, recent studies also suggest that nicotine enhances programmed cell death both in in vitro and in vivo systems 22-24 also at concentration levels such as those reported in smokers. 25,26 This study investigated the effects of constantly infused nicotine and buproprion on cell genesis (by determining BrDu incorporation) and DNA fragmentation in the DG. The nicotine dose chosen (4 mg/kg/day) results in blood nicotine concentrations (approximately 80 ng/ml) that would only be found in heavy smokers while the dose of buproprion (30 mg/kg/day) chosen was that reported to have antidepressant activity in the rat. 27 A 21-day chronic drug administration schedule was consistent with the time course for the therapeutic action of antidepressant treatment. Materials and methods Subjects Male Sprague-Dawley rats (Harlan Industries, UK), weighing 260-320g at the start of the experiment, were used. Rats were housed, two per cage, in a temperature-controlled (21°C) and humidity-controlled (50%±10%) environment on a 12 hour light/dark cycle with lights on at 6.00 am. Food and water were provided ad libitum. All the experiments were conducted during the light phase of the cycle and were in accordance with the UK Home Ofice regulations and covered by a Home Ofice project licence. Drug treatment Rats were divided into four groups: a control group that received saline only (S-S), a nicotine-saline group that received 4 mg/kg/day nicotine and saline (N-S), a buproprion-saline group that received 30 mg/kg/day buproprion and saline (B-S), and a nicotine-buproprion group that received 4 mg/kg/day nicotine and 30 mg/kg/day (N-B) (Table 1). All reagents were purchased