Prolonging the Reduction of Nicotine Self-Administration in Rats by Coadministering Chronic Nicotine With Amitifadine, a Triple Monoamine Reuptake Inhibitor With CYP2B6 Inhibitory Actions

Abstract

Introduction Existing treatments can aid tobacco smoking cessation, but they have low efficacy. Because there is a network of neural systems involved in tobacco addiction, combination treatments may provide greater efficacy. Chronic nicotine and amitifadine have each been shown to significantly reduce nicotine self-administration in rats. This study was conducted to determine if the combination of chronic nicotine with amitifadine, a triple monoamine reuptake inhibitor with CYP2B inhibitory effects, would reduce nicotine self-administration to a greater extent than either alone or placebo. Methods This study tested the combination of nicotine plus amitifadine in young adult female Sprague-Dawley rats self-administering nicotine (0.03 mg/kg/infusion). This combination was compared with each treatment alone and the vehicle during continuing nicotine self-administration as well as during resumption of self-administration after a week of enforced abstinence, modeling a quit attempt. Finally, we studied the residual effects of these therapies after discontinuation of treatment. Results Treatment with either chronic nicotine or amitifadine alone significantly reduced nicotine self-administration relative to controls. The combination of the treatments significantly enhanced this effect. After treatment withdrawal, all of the groups showed increases in nicotine self-administration, but only the combined treatment group remained significantly below control rates of nicotine self-administration. Conclusions This study showed the promise of amitifadine as a possible new treatment for smoking cessation and suggested that amitifadine is more effective when given with chronic nicotine. The improved efficacy of the amitifadine and nicotine combination may be potentiated by amitifadine’s inhibitory effects on CYP2B, which slows nicotine metabolism. Implications This study replicated the effects that chronic nicotine or chronic amitifadine, a triple reuptake inhibitor, significantly reduces nicotine self-administration in rats. It extends those findings by showing that the combination of chronic nicotine plus amitifadine causes significantly greater reduction in nicotine self-administration than either drug treatment alone. The combination of chronic amitifadine and chronic nicotine also causes a persistent significant reduction in nicotine self-administration after the end of treatment. The amitifadine and nicotine treatment should be assessed in humans to determine whether this combination provides greater efficacy in smoking cessation than transdermal nicotine treatment alone.

Tobacco and ADHD: A Role of MAO-Inhibition in Nicotine Dependence and Alleviation of ADHD Symptoms

“…The role of MAO-inhibitors on smoking cessation is also likely to have been historically under-scrutinized. MAO-inhibitors may increase the reinforcing value of low doses of nicotine ( Smith et al, 2016 ) and Levin et al (2020) found that the joint administration of nicotine with amitifadine, a triple monoamine reuptake inhibitor, greatly aids smoking cessation ( Levin et al, 2020 ). All studies together support the role of both tobacco smoke compounds and e-cigarette flavourants in MAO-inhibition and dopaminergic systems.…”

“…The authors of this current scoping review sought to explore whether nicotine alone may not be a sufficient mechanism for the relationship between ADHD + dopaminergic dysregulation in smoking initiation and dependence. The important role of MAO-inhibitors is supported by evidence suggesting that MAO-B is inhibited in the brains of smokers in the general population, thereby increasing dopamine availability ( Fowler et al, 1996 ) and that the joint administration MAO-inhibitors, greatly aid smoking cessation ( Smith et al, 2016 ; Levin et al, 2020 ).…”