Effects of chronic varenicline treatment on nicotine, cocaine, and concurrent nicotine+cocaine self-administration

Abstract

Nicotine dependence and cocaine abuse are major public health problems, and most cocaine abusers also smoke cigarettes. An ideal treatment medication would reduce both cigarette smoking and cocaine abuse. Varenicline is a clinically available, partial agonist at α4β2* and α6β2* nicotinic acetylcholine receptors (nAChRs) and a full agonist at α7 nAChRs. Varenicline facilitates smoking cessation in clinical studies and reduced nicotine self-administration, and substituted for the nicotine-discriminative stimulus in preclinical studies. The present study examined the effects of chronic varenicline treatment on self-administration of IV nicotine, IV cocaine, IV nicotine+cocaine combinations, and concurrent food-maintained responding by five cocaine- and nicotine-experienced adult rhesus monkeys (Macaca mulatta). Varenicline (0.004-0.04 mg/kg/h) was administered intravenously every 20 min for 23 h each day for 7-10 consecutive days. Each varenicline treatment was followed by saline-control treatment until food- and drug-maintained responding returned to baseline. During control treatment, nicotine+cocaine combinations maintained significantly higher levels of drug self-administration than nicotine or cocaine alone (P<0.05-0.001). Varenicline dose-dependently reduced responding maintained by nicotine alone (0.0032 mg/kg/inj) (P<0.05), and in combination with cocaine (0.0032 mg/kg/inj) (P<0.05) with no significant effects on food-maintained responding. However, varenicline did not significantly decrease self-administration of a low dose of nicotine (0.001 mg/kg), cocaine alone (0.0032 and 0.01 mg/kg/inj), or 0.01 mg/kg cocaine combined with the same doses of nicotine. We conclude that varenicline selectively attenuates the reinforcing effects of nicotine alone but not cocaine alone, and its effects on nicotine+cocaine combinations are dependent on the dose of cocaine.

Figure 1

Effects of varenicline on cocaine and nicotine self-administration: each dose of cocaine or nicotine is shown above each set of bar graphs. Ordinate: the number of cocaine or nicotine injections per day for the last three days of the treatment period. Drug self-administration during saline treatment is shown as open bars. Drug self-administration during varenicline treatment is shown as gray bars (0.004 mg/kg/h) and black bars (0.04 mg/kg/h). The top row shows drug self-administration when low minimally reinforcing doses of cocaine and nicotine were available. The bottom row shows drug self-administration when higher reinforcing doses of cocaine and nicotine were available. The ANOVA found a significant effect of varenicline on self-administration of 0.0032 mg/kg/inj nicotine (F(2,6)=6.43; p=0.03) during treatment with 0.04 mg/kg/h varenicline (p=0.02). Varenicline did not significantly alter self-administration of 0.0032 or 0.01 mg/kg/inj cocaine and 0.001 mg/kg/inj nicotine (all Fs<1.73; ps=0.28–0.44). Each data point represents the mean±SEM of 3–4 monkeys. *p<0.05 vs baseline.

Figure 2

Effects of varenicline on cocaine+nicotine self-administration: each dose of cocaine+nicotine is shown above each set of bar graphs. Ordinate: the number of cocaine+nicotine injections per day for the last three days of the treatment period. Drug self-administration during saline treatment is shown as open bars. Drug self-administration during varenicline treatment is shown as gray bars (0.004 mg/kg/h) and black bars (0.04 mg/kg/h). The top row shows drug self-administration when low minimally reinforcing doses of cocaine+nicotine were available. The bottom row shows drug self-administration when higher reinforcing doses of cocaine+nicotine were available. The ANOVA found a significant effect of varenicline (0.04 mg/kg/h; p=0.025) on self-administration of 0.0032 mg/kg/inj cocaine+0.0032 mg/kg/inj nicotine (F(2,8)=4.936; p=0.04) but not on 0.0032 mg/kg/inj cocaine+0.001 mg/kg/inj nicotine, 0.01 mg/kg/inj cocaine+0.001 mg/kg/inj nicotine, or 0.01 mg/kg/inj cocaine+0.0032 mg/kg/inj nicotine (all Fs<1.08; ps=0.38–0.44). Each data point represents the mean±SEM of 4–5 monkeys. *p<0.05 vs baseline.

Figure 3

Comparison of the number of injections of cocaine and nicotine alone with cocaine+nicotine combinations during saline control treatment: Abscissa: doses of cocaine (0.0032 or 0.01 mg/kg/inj) shown as light gray rectangles; doses of nicotine (0.001 or 0.0032 mg/kg/inj) shown as dark gray rectangles; and the same doses of cocaine and nicotine in combination are shown as black rectangles. Ordinate: number of drug injections per day during saline treatment. Each data point is the average (±SEM) of 5 monkeys during the last three days of each drug condition. One-way repeated measures analysis of variance (ANOVA) with Fisher's LSD post hoc tests were used to determine whether self-administration of the cocaine plus nicotine combinations was significantly higher than the same doses of nicotine or cocaine alone as measured by the number of injections per day. The ANOVAs found a significant main effect of reinforcer when 0.0032 mg/kg cocaine, 0.001 mg/kg/inj nicotine, and 0.0032 mg/kg/inj cocaine+0.001 mg/kg/inj nicotine were compared (F(2,8)=5.495; p=0.03) and when 0.01 mg/kg/inj cocaine, 0.0032 mg/kg/inj nicotine, and 0.01 mg/kg/inj cocaine+0.0032 mg/kg/inj nicotine were compared (F(2,8)=16.97; p=0.001). Post hoc tests found that self-administration of the 0.0032 mg/kg/inj cocaine+0.001 mg/kg/inj nicotine combination was significantly greater than either 0.0032 mg/kg/inj cocaine or 0.001 mg/kg/inj nicotine alone (ps=0.029 and 0.016, respectively). Further, self-administration of 0.01 mg/kg/inj cocaine+0.0032 mg/kg/inj nicotine was significantly greater than 0.0032 mg/kg/inj nicotine alone (p=0.0025) but not 0.01 mg/kg/inj cocaine alone (p−0.725) *=p<0.05.