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 2-nicotinic acetylcholine receptor subunit knockout mice. Finally, it was found that, whereas naïve rats did not readily self-administer nicotine (10 g/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.
Anne-Sophie Villégier1,2, Lucas Salomon1, Sylvie Granon3, Jean-Pierre Changeux3, James D Belluzzi2, Frances M Leslie2 and Jean-Pol Tassin1
1. 1Inserm U.114, Collège de France, Place Marcelin Berthelot,Paris, France
2. 2Department of Pharmacology, School of Medicine and Transdisciplinary Tobacco Use Research Center, University of California, Irvine, CA, USA
3. 3Laboratoire de Neurobiologie Moléculaire, C.N.R.S., Récepteurs et Cognition, Institut Pasteur, Paris, France
Correspondence: Dr J-P Tassin, Inserm U.114, Collège de France, 11, Place Marcelin Berthelot, 75231 Paris, France. Tel: +33 1 44271231; Fax: +33 1 44271260; E-mail: jean-pol.tassin@college-de-franc…
Received 29 July 2005; Revised 28 September 2005; Accepted 21 October 2005; Published online 14 December 2005.