Monoamine Oxidase Inhibitors Allow Locomotor and Rewarding Responses to Nicotine

Abstract

Although nicotine is generally considered to be the main compound responsible for the addictive properties of tobacco, experimental data indicate that nicotine does not exhibit all the characteristics of other abused substances, such as psychostimulants and opiates. For example, nicotine is only a weak locomotor enhancer in rats and generally fails to induce a locomotor response in mice. This observation contradicts the general consensus that all drugs of abuse release dopamine in the nucleus accumbens, a subcortical structure, and thus increase locomotor activity in rodents. Because tobacco smoke contains monoamine oxidase inhibitors (MAOIs) and decreases MAO activity in smokers, we have combined MAOIs with nicotine to determine whether it is possible to obtain a locomotor response to nicotine in C57Bl6 mice. Among 15 individual or combined MAOIs, including harmane, norharmane, moclobemide, selegiline, pargyline, clorgyline, tranylcypromine and phenelzine, only irreversible inhibitors of both MAO-A and -B (tranylcypromine, phenelzine, and clorgyline + selegiline) allowed a locomotor response to nicotine. The locomotor stimulant interaction of tranylcypromine and nicotine was absent in b2-nicotinic acetylcholine receptor subunit knockout mice. Finally, it was found that, whereas naïve rats did not readily selfadminister nicotine (10 mg/kg/injection), a robust self-administration of nicotine occurred when animals were pretreated with tranylcypromine (3 mg/kg). Our data suggest that MAOIs contained in tobacco and tobacco smoke act in synergy with nicotine to enhance its rewarding effects.

Acetaldehyde, a Major Constituent of Tobacco Smoke, Enhances Behavioral, Endocrine, and Neuronal Responses to Nicotine in Adolescent and Adult Rats

“…However, the underlying mechanisms are not well understood. Although nicotine is believed to be the major psychoactive component in tobacco, nicotine's rewarding and locomotor stimulant effects in animal studies are weaker than that of other psychostimulants (Manzardo et al, 2002;Villegier et al, 2006). Given that nicotine is not the only psychoactive ingredient in tobacco, other tobacco constituents may also contribute to smoking behaviors.…”

Inhibition of Monoamine Oxidases Desensitizes 5-HT1AAutoreceptors and Allows Nicotine to Induce a Neurochemical and Behavioral Sensitization

“…were kept identical with previous experiments (Auclair et al, 2004). Doses of nicotine (1 mg/kg, s.c.; salt instead of base) and tranylcypromine (6 mg/kg instead of 10 mg/kg) were decreased because of repeated treatments (Villégier et al, 2006a). SCH23390 was used at 0.2 mg/kg (intraperitoneally), a dose which blocks the development of behavioral and neurochemical sensitization to 2 mg/kg D-amphetamine (Salomon et al, 2006).…”

“…Spontaneous activity was recorded for 120 min (habituation to the experimental procedure), and then mice were injected intraperitoneally with D-amphetamine or p-chloroamphetamine or tranylcypromine or nicotine or tranylcypromine plus nicotine or WAY 100635 or WAY 100635 plus nicotine or 8-OHDPAT or 8-OHDPAT plus nicotine, and locomotor responses were recorded for an additional 200 min period. Injection of nicotine occurred 100 min after injection of tranylcypromine (Villégier et al, 2006a), 30 min after injection of WAY 100635, and 60, 100, or 120 min after injection of 8-OHDPAT.…”

“…A few years ago, we showed that MAOI pretreatment allows the maintenance of behavioral sensitization to nicotine in rats (Villégier et al, 2003), thus suggesting a role of MAOIs in the addictive properties of tobacco. Later, it was found that a pretreatment with tranylcypromine, a potent and irreversible MAOI, could trigger a locomotor and rewarding response to nicotine in mice (Villégier et al, 2006b) and dramatically increase nicotine self-administration in rats (Guillem et al, 2005;Villégier et al, 2006a).…”

Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine

“…Second, research using selective MAO-A and MAO-B inhibitors has suggested that it is MAO-A, and not MAO-B, inhibition that increases nicotine self-administration (Guillem et al, 2006), although MAO activity was not measured to confirm selective inhibition of MAO isoforms. Third, the majority of research in this area has used large doses of MAO inhibitors, which likely fully inhibit MAO (Guillem et al, 2005(Guillem et al, , 2006Villegier et al, 2003Villegier et al, , 2006Villegier et al, , 2007Villegier et al, , 2011. Thus, it is unknown whether partial inhibition, in the range seen in chronic smokers, increases the reinforcing value of nicotine.…”