Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats

Abstract

Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats. These effects were more prominent in rats selected for high responsiveness to novelty than in rats with low responsiveness to novelty. The results suggest that the inhibition of MAO activity by compounds present in tobacco smoke may combine with nicotine to produce the intense reinforcing properties of cigarette smoking that lead to addiction.

Figure 1.

Dose–response effects of acute MAOI treatments on spontaneous locomotor activity (white, hatched, and black bars show vehicle, TCP, and PLZ pretreatment, respectively). Locomotor activity (mean photocell interruptions ± SEM) was recorded for 3 h. **p<0.01 and ***p < 0.001, significant difference when compared with vehicle-injected rats.

Figure 2.

Plasma nicotine (left) and cotinine (right) (in nanograms per milliliter) after repeated intravenous injections of nicotine (30 μg/kg per injection, free base) to mimic nicotine SA. Rats were pretreated for 5 d with vehicle (circles; n = 4), TCP (triangles; 1.5 mg · kg^–1 · d^–1; n = 4), or PLZ (squares; 2 mg · kg^–1 · d^–1; n = 5). On the fifth day, rats received MAOI treatment, followed 60 min later by intravenous injections of nicotine. Error bars represent SEM.

Figure 3.

Evaluation of locomotor reactivity to novelty of the rats, which will be used in nicotine and food-maintained responding. Reactivity to novelty was assessed before any pharmacological treatment (vehicle, TCP, and PLZ), by measuring locomotor activity for 2 h in a novel environment (mean photocell interruptions ± SEM). LR and HR rats corresponded, respectively, to the lower third and higher third of scores of the subject sample. The middle score subjects(⅓)were discarded from the study. LR-Vehicle (n=23), LR-TCP (n=23), and LR-PLZ (n = 23) and HR-Vehicle (n = 21), HR-TCP (n = 21), and HR-PLZ (n = 22). ***p < 0.001, significant difference between groups as revealed by Newman–Keuls post hoc test.

Figure 4.

Effects of vehicle (circles), TCP (triangles; 1.5mg · kg^–1 · d^–1), and PLZ (squares; 2mg · kg^–1 · d^–1) pretreatment on acquisition of nicotine SA in LR and HR animals on each of the 23 d of testing under fixed-ratio schedules of reinforcement (FR1, FR2, and FR5). Data are shown as mean responding ± SEM on the active (filled symbols) and inactive (open symbols) holes.

Figure 5.

Effects of vehicle, TCP (1.5 mg · kg^–1 · d^–1), and PLZ (2 mg · kg^–1 · d^–1) pretreatment on stable nicotine self-administration under the FR5 schedule of reinforcement in LR and HR animals. Mean scores ± SEM during the last 3 d of the FR5. Each self-administration session lasted for 2 h. a, Effects of MAOI pretreatment (white, hatched, and black bars show vehicle, TCP, and PLZ pretreatment, respectively) on the number of responses on the active hole (top) and on the inactive hole (bottom). *p < 0.05, **p < 0.01, and ***p < 0.001, significant difference in response rates between the two holes in the same group of rats. ⁺p < 0.05 and ⁺⁺⁺p < 0.001, significant difference in responses rates between each subgroup as revealed by the Newman–Keuls post hoc test. b, Effects of MAOI pretreatment on the number of nicotine infusions (30 μg/kg per infusion). ⁺⁺p < 0.01 and ⁺⁺⁺p < 0.001, significant difference in nicotine intake between each subgroup as revealed by the Newman–Keuls post hoc test. Error bars represent SEM.

Figure 6.

Effects of vehicle, TCP (1.5 mg · kg^–1 · d^–1), and PLZ (2 mg · kg^–1 · d^–1) pretreatment under the PR schedule of reinforcement on nicotine self-administration (a) and food-maintained responding (b) in LR and HR animals. Values represent the mean number of nose-poke responses (a) for nicotine self-administration and lever-press responses (b) for food-maintained responding, corresponding to the final ratio attained (breaking point) during the 5 d of the PR schedule of reinforcement. Vehicle, White bars; TCP, hatched bars; PLZ, black bars. ⁺p < 0.05 and ⁺⁺⁺p < 0.001, significant difference between each subgroup as revealed by the Newman–Keuls post hoc test. Error bars represent SEM.

Figure 7.

Effects of vehicle (circles), TCP (triangles; 1.5 mg · kg^–1 · d^–1), and PLZ (squares; 2 mg · kg^–1 · d^–1) on nicotine dose–response function in LR (a, b) and HR (c, d) animals under the FR5 schedule of reinforcement. Each self-administration session lasted for 2 h. a, c, Effects of MAOI pretreatment on the number of responses on the active hole (mean ± SEM) during the last day of each dose. *p < 0.05 and **p < 0.01, significant difference in response rates between each group as revealed by the Newman–Keuls post hoc test. b, d, Effects of MAOI pretreatmentonthetotalintakeofnicotine(mean±SEM)earnedateachunitdose. *p<0.05 and **p < 0.01, significant difference in nicotine intake between each group, as revealed by the Newman–Keuls post hoc test. The training dose was 30 μg/kg per infusion.