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

Abstract

The Food and Drug Administration (FDA) has the authority to regulate cigarette smoke constituents, and a reduction in nicotine content might benefit public health by reducing the prevalence of smoking. Research suggests that cigarette smoke constituents that inhibit monoamine oxidase (MAO) may increase the reinforcing value of low doses of nicotine. The aim of the present experiments was to further characterize the impact of MAO inhibition on the primary reinforcing and reinforcement enhancing effects of nicotine in rats. In a series of experiments, rats responded for intravenous nicotine infusions or a moderately-reinforcing visual stimulus in daily 1-h sessions. Rats received pre-session injections of known MAO inhibitors. The results show that (1) tranylcypromine (TCP), a known MAO inhibitor, increases sensitivity to the primary reinforcing effects of nicotine, shifting the dose-response curve for nicotine to the left, (2) inhibition of MAO-A, but not MAO-B, increases low-dose nicotine self-administration, (3) partial MAO-A inhibition, to the degree observed in chronic cigarette smokers, also increases low-dose nicotine self-administration, and (4) TCP decreases the threshold nicotine dose required for reinforcement enhancement. The results of the present experiments suggest cigarette smoke constituents that inhibit MAO-A, in the range seen in chronic smokers, are likely to increase the primary reinforcing and reinforcement enhancing effects of low doses of nicotine. If the FDA reduces the nicotine content of cigarettes, then variability in constituents that inhibit MAO-A could impact smoking.

The nicotine-degrading enzyme NicA2 reduces nicotine levels in blood, nicotine distribution to brain, and nicotine discrimination and reinforcement in rats

“…Tobacco pH may influence smoking behavior but does so by modifying nicotine absorption [ 1 ]. Monoamine inhibitors present in tobacco can modify nicotine’s effects and enhance nicotine self-administration in rats but are not by themselves reinforcing [ 35 ]. In contrast, the evidence that the nicotine content of cigarettes drives tobacco use is abundant [ 1 , 36 ].…”

Self-administration of Smokeless Tobacco Products in Rats

“…Examination of other nicotine unit doses also represents an important area for future work, as effects of smoke extracts and non-nicotine constituents on nicotine reinforcement can depend on the nicotine unit dose. 6,12,48 Nevertheless, to the extent that manipulating unit price via increasing the FR response requirement is functionally equivalent to reducing the unit dose, 49 the similar consumption of nicotine alone and extracts during the current FR escalation procedure would be expected to generalize to a dose-reduction protocol.…”

Reduced-Nicotine Cigarettes in Young Smokers: Impact of Nicotine Metabolism on Nicotine Dose Effects

“…However, that relief of craving and withdrawal was nicotine-dose dependent in normal metabolizers indicates that such relief may be related to the nicotine-dosedependent effects on both dopamine release in the ventral striatum (Brody et al, 2009a) and nicotinic receptor occupancy (Brody et al, 2009b). Importantly, in both normal and slow metabolizers, effects of smoking cigarettes delivering very low doses of nicotine may also involve non-nicotine constituents of cigarette smoke, such as the harmala alkaloids, which inhibit monoamine oxidase A, and increase the reinforcing effects of low, but not high, doses of nicotine in rats (Smith et al, 2016).…”