Effects of MAO inhibition and a combination of minor alkaloids, β-carbolines, and acetaldehyde on nicotine self-administration in adult male rats

Abstract

Introduction Although nicotine is the primary reinforcing constituent in cigarettes, there is evidence that other constituents in cigarette smoke may interact with nicotine to reinforce smoking behavior. Methods The present experiments investigated whether a novel combination of these cigarette smoke constituents would increase nicotine self-administration in adult male rats. The constituents included five minor alkaloids (anabasine, nornicotine, cotinine, myosmine, and anatabine), two β-carbolines (harman and norharman), and acetaldehyde. All doses were indexed to be proportional to concentrations in cigarette smoke given a standard dose of nicotine used in rodent self-administration, or ten times higher than this standard. To model MAO inhibition seen in chronic smokers, some groups received separate injections of tranylcypromine prior to each self-administration session. Results Tranylcypromine increased low-dose nicotine self-administration independent of other smoke constituents, which had no effect on self-administration behavior. The effect of tranylcypromine was confirmed across a large range of reinforcement schedules. The effect of tranylcypromine on low-dose nicotine self-administration was observed regardless of whether the injection was delivered 1-hr or 23-hrs prior to the self-administration session, consistent with the interpretation that MAO inhibition was responsible for the increase in self-administration, instead of acute off-target effects. Conclusions These data suggest that this cocktail of constituents does not significantly alter the primary reinforcing effects of nicotine, but constituents that inhibit MAO may increase the primary reinforcing effects of nicotine, especially at low doses.

Reducing the nicotine content of combusted tobacco products sold in New Zealand

“…Nicotine reduction is not intended to address all the reasons people smoke, but instead targets the neuropharmacological effects of combusted tobacco that are widely believed to be responsible for dependence. Although some other constituents of tobacco are psychoactive, current evidence from animal studies suggests that these other constituents, in the doses found in tobacco, would have little impact on behaviour either alone or in combination with low doses of nicotine 48. One non-nicotine effect of tobacco smoke—inhibition of monoamine oxidase—may increase sensitivity to the reinforcing effects of low doses of nicotine, but this effect does not appear to be sufficient to maintain rat self-administration if nicotine is adequately reduced 49.…”

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

“…MAO inhibition has been shown to increase nicotine self-administration on fixed-ratio (FR) and progressive-ratio schedules (Guillem et al, 2005;Smith et al, 2015;Villegier et al, 2007). However, the high doses of TCP used by some researchers have been shown to increase nicotine self-administration through acute, off-target effects (eg, monoamine release) rather than the long-lasting effect of MAO inhibition (Lotfipour et al, 2011;Villegier et al, 2011).…”

“…Although MAO inhibition clearly increases the primary reinforcing effect of nicotine under some conditions (Guillem et al, 2005;Smith et al, 2015), more research is needed. First, the impact of MAO inhibition across different nicotine doses is not fully understood.…”

“…There are over 8000 non-nicotine constituents in cigarette smoke (Rodgman and Perfetti, 2013), and researchers have used a rodent model of nicotine self-administration to investigate whether these constituents might reinforce behavior or interact with nicotine to reinforce behavior (Arnold et al, 2014;Bardo et al, 1999;Belluzzi et al, 2005;Brennan et al, 2015;Clemens et al, 2009;Costello et al, 2014;Smith et al, 2015). Cigarette smoke constituents have been shown to inhibit monoamine oxidase (MAO), an enzyme involved in the oxidative degradation of monoamines.…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…Another critical consideration for ongoing research will be a closer examination of gender differences and their influence on stress-mediated relapse. Indeed, emerging data from multiple studies continue to provide evidence for gender-specific differences in successful quit attempts in smokers [19] as well as sex-specific effects regarding the role of stress in nicotine use and relapse in preclinical models and in humans [261-263]. Evidence from smokers suggests that men are more sensitive to the pharmacological effects of nicotine, where women are more sensitive to smoking-related cues [264, 265], and these gender differences have important implications for smoking relapse and cessation strategies [266].…”