Cigarette Smoke Extract, but Not Electronic Cigarette Aerosol Extract, Inhibits Monoamine Oxidase in vitro and Produces Greater Acute Aversive/Anhedonic Effects Than Nicotine Alone on Intracranial Self-Stimulation in Rats

Abstract

Conventional tobacco cigarettes appear to have greater abuse liability than non-combusted products such as electronic cigarettes (ECs) and nicotine replacement therapy (NRT). This may be due to the higher levels of behaviorally active non-nicotine constituents [e.g., monoamine oxidase (MAO) inhibitors such as β-carbolines] in cigarette smoke (CS) compared to non-combusted products. To evaluate this hypothesis, the current studies compared the relative abuse liability of CS and EC aerosol extracts containing nicotine and a range of non-nicotine constituents to that of nicotine alone (NRT analog) using intracranial self-stimulation (ICSS) in rats. Effects of formulations on brain MAO activity in vitro and ex vivo were also studied to evaluate the potential role of MAO inhibition in the ICSS study. CS extract contained higher levels of several behaviorally active non-nicotine constituents (e.g., the β-carbolines norharmane and harmane) than EC extract. Nicotine alone reduced ICSS thresholds at a moderate nicotine dose, suggesting a reinforcement-enhancing effect that may promote abuse liability, and elevated ICSS thresholds at a high nicotine dose, suggesting an aversive/anhedonic effect that may limit abuse liability. CS extract elevated ICSS thresholds to a greater degree than nicotine alone at high nicotine doses. Effects of EC extract on ICSS did not differ from those of nicotine alone. Finally, CS extract significantly inhibited MAO-A and MAO-B activity in vitro, whereas EC extract and nicotine alone did not. None of the formulations inhibited MAO measured ex vivo. These findings indicate greater acute aversive/anhedonic effects for CS extract compared to nicotine alone, suggesting lower abuse liability. Although confirmation of our findings using other dosing regimens, preclinical addiction models, and tobacco product extracts is needed, these findings suggest that the centrally-mediated effects of MAO inhibitors and other non-nicotine constituents may not account for the greater abuse liability of cigarettes compared to non-combusted products. Nonetheless, identifying the specific constituent(s) mediating the effects of CS extracts in this study could help clarify mechanisms mediating tobacco addiction and inform FDA product standards.

Chronic exposure to cigarette smoke extract increases nicotine withdrawal symptoms in adult and adolescent male rats

“…Although substantial work has been done on the identity of non-nicotine constituents that impact nicotine reinforcement and reward [ 24 , 26 , 58 – 62 ], there are few studies that have looked at the impact of individual constituents on nicotine withdrawal. One exception is monoamine oxidase inhibitors (MAOIs) in tobacco which reduce enzyme activity in the brains of smokers [ 63 ] and are present in CSE extracts [ 24 , 64 ]. In rats, chronic MAOI treatment induces a prolonged conditioned placed aversion associated with nicotine withdrawal [ 25 ].…”

“…In the present study, we have confirmed that non-nicotine tobacco constituents in CSE administered intravenously enhance both physical and affective symptoms of nicotine withdrawal in adult rats. We have previously shown that these constituents do not impact nicotine self-administration, but do enhance reinstatement induced by the pharmacological stressor, yohimbine [ 24 , 27 ] and elevate and increase intracranial self-stimulation thresholds to a greater degree than high doses of nicotine alone [ 64 ]. Thus, tobacco constituents appear to increase the negative impact of withdrawal from chronic nicotine.…”

β-Carboline Alkaloids in Soy Sauce and Inhibition of Monoamine Oxidase (MAO)

“…Naturally occurring β-carboline alkaloids have been identified in the inhibition of MAO by cigarette smoke [ 21 , 22 ], coffee [ 23 ] and raisins [ 24 ]. The inhibition of MAO in smokers and coffee drinkers might be linked with some biological actions, such as the addictive properties of cigarettes and depression [ 25 , 26 ] and the lowest incidence of Parkinson’s disease (PD) [ 27 , 28 , 29 , 30 ]. More research is currently needed to study the effects of diet and environmental factors on MAO enzymes.…”