Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors

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Abstract

Drugs of abuse, such as d-amphetamine or nicotine, are generally considered as acting through an increased release of dopamine in a subcortical structure, the nucleus accumbens, thus inducing locomotor hyperactivity in rats. Following repeated treatments, the same drugs induce a progressive increase in locomotor response called behavioral sensitization. This process has been suggested to play a role in the acquisition and maintenance of addictive behaviors. Here we show that whereas behavioral sensitization to d-amphetamine (0.5 and 0.75 mg/kg) stays constant following three consecutive periods of withdrawal (15, 30 and 30 days), the same experimental conditions completely abolish behavioral sensitization to 0.3 and 0.5 mg/kg nicotine. Indeed, following these periods of withdrawal, locomotor responses to nicotine are identical to those obtained at the first nicotine injection or after repeated saline injections.

However, when a monoamine oxidases inhibitor (MAOI), tranylcypromine (3 mg/kg) or pargyline (30 mg/kg), is co-injected with nicotine, behavioral sensitization is maintained despite submission of the animals to the same withdrawal experimental design. Since tobacco smoke is known to contain many compounds including MAOIs, our data suggest that addictive properties of tobacco may not be limited to nicotine. We propose that MAOIs potentiate effects of nicotine on monoamines release.

Introduction

Tobacco is probably one of the most abused reinforcing agents in humans, and its motivating power is supported by the difficulty encountered when a smoker attempts to quit (Balfour et al., 2000). Although the mechanisms underlying addiction to tobacco are not completely understood, it is generally admitted that nicotine is the major addictive compound contained in tobacco smoke Balfour et al., 2000, Dani and Heinemann, 1996, Di Chiara, 2000. Nevertheless, clinical studies show that abusers of pure nicotine, i.e., of nicotine isolated from tobacco, do not exist. Furthermore, nicotine administration only incompletely ameliorates withdrawal symptoms and does not prevent a high rate of relapse (Pierce and Gilpin, 2002). In addition, denicotinized cigarettes were found to reduce craving and withdrawal signs, strongly suggesting that agents other than nicotine are involved in tobacco addiction (Pickworth et al., 1999).

Addictive effects of drugs of abuse, such as psychostimulants, opiates and possibly nicotine, have been related to an increased meso-limbic dopaminergic transmission, thus inducing locomotor hyperactivity in rodents (Di Chiara and Imperato, 1988). Moreover, following repeated treatments, these drugs also induce a behavioral sensitization, i.e., an increase in locomotor response, a phenomenon that stays constant even after withdrawal (Robinson and Becker, 1986). This process has been suggested to play a role in the acquisition and maintenance of addictive behaviors (Robinson and Becker, 1986), the long-lasting nature of behavioral sensitization being correlated with relapse and craving observed in humans even after long withdrawal periods (Robinson and Berridge, 1993).

Actually, there is some behavioral and biochemical indications suggesting that nicotine may act differently from other drugs of abuse. For example, although psychostimulants and opiates induce locomotor hyperactivity both in rats and mice, nicotine generally fails to do so in mice (Marks et al., 1983). Moreover, unlike other drugs of abuse, nicotine desensitizes meso-limbic dopaminergic transmission following repeated treatments Vezina et al., 1992, Pidoplichko et al., 1997, and the dopaminergic nature of locomotor hyperactivity and behavioral sensitization induced in rats by nicotine is still a matter of debate Vezina et al., 1994, Boye et al., 2001.

For all these reasons, we have tested more thoroughly the behavioral effects of nicotine and compared these data with those obtained with a major addictive psychostimulant, d-amphetamine. First, kinetics of locomotor responses were analyzed after acute and repeated treatments with each compound. Then, animals were submitted to three consecutive periods of withdrawal to test maintenance of behavioral sensitization. Finally, because tobacco smoke is known to contain a number of compounds among which monoamine oxidases inhibitors (MAOIs) have been the focus of special interest Poindexter and Carpenter, 1962, Breyer-Pfaff et al., 1996, Rommelspacher et al., 2002, the effects on the maintenance of behavioral sensitization to nicotine of two MAOIs, tranylcypromine and pargyline, were tested.

Section snippets

Subjects

Male Sprague–Dawley rats (Iffa-Credo, Lyon, France) weighing 240–260 g on arrival were maintained on a 12 h light/12 h dark cycle (light on between 7 a.m. and 7 p.m.) at constant temperature (22 °C), with food and water ad libitum. Animals were housed by groups of four and were habituated to their home cages for at least one week before the experiments. Rats were treated in accordance with the Guide for Care and Use of Laboratory Animals established by the National Institutes of Health and with

Effects of acute and repeated injections of d-amphetamine and nicotine on locomotor activities

As expected, both acute d-amphetamine (0.5 and 0.75 mg/kg) and nicotine (0.3–0.8 mg/kg) injections induce locomotor hyperactivity in rats (Fig. 1A) (P=.019 and P<.001 for 0.5 and 0.75 mg/kg d-amphetamine, respectively, and P=.0098, P<.0001 and P=.0115 for 0.3, 0.5 and 0.8 mg/kg nicotine, respectively, when compared with saline-treated animals, Student's t test). No difference in locomotor responses was observed between 0.5 and 0.8 mg/kg nicotine injections [F(1,126)=0.03, P=.86, two-way ANOVA].

Discussion

The first finding of this study is that in contrast to that observed with d-amphetamine, behavioral sensitization induced by repeated injections of nicotine in rats is short-lasting. The second finding is that this transient behavioral sensitization becomes long-lasting when a MAOI, such as tranylcypromine or pargyline, is co-injected with nicotine. Altogether, if one assumes that maintenance of behavioral sensitization is related to addiction, our data suggest that both nicotine and MAOIs

Acknowledgments

Anne-Sophie Villégier has received a fellowship from “Fondation Gilbert Lagrue”.

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