Repeated administration of an acetylcholinesterase inhibitor attenuates nicotine taking in rats and smoking behavior in human smokers

Abstract

Tobacco smoking remains the leading cause of preventable death worldwide and current smoking cessation medications have limited efficacy. Thus, there is a clear need for translational research focused on identifying novel pharmacotherapies for nicotine addiction. Our previous studies demonstrated that acute administration of an acetylcholinesterase inhibitor (AChEI) attenuates nicotine taking and seeking in rats and suggest that AChEIs could be repurposed for smoking cessation. Here, we expand upon these findings with experiments designed to determine the effects of repeated AChEI administration on voluntary nicotine taking in rats as well as smoking behavior in human smokers. Rats were trained to self-administer intravenous infusions of nicotine (0.03 mg kg(-1) per 0.59 ml) on a fixed-ratio-5 schedule of reinforcement. Once rats maintained stable nicotine taking, galantamine or donepezil was administered before 10 consecutive daily nicotine self-administration sessions. Repeated administration of 5.0 mg kg(-1) galantamine and 3.0 mg kg(-1) donepezil attenuated nicotine self-administration in rats. These effects were reinforcer-specific and not due to adverse malaise-like effects of drug treatment as repeated galantamine and donepezil administration had no effects on sucrose self-administration, ad libitum food intake and pica. The effects of repeated galantamine (versus placebo) on cigarette smoking were also tested in human treatment-seeking smokers. Two weeks of daily galantamine treatment (8.0 mg (week 1) and 16.0 mg (week 2)) significantly reduced smoking rate as well as smoking satisfaction and reward compared with placebo. This translational study indicates that repeated AChEI administration reduces nicotine reinforcement in rats and smoking behavior in humans at doses not associated with tolerance and/or adverse effects.

Figure 1

Repeated administration of galantamine dose-dependently attenuated nicotine, but not sucrose, self-administration in rats. Galantamine pretreatment significantly attenuated total active lever responses (a) and total nicotine infusions (b) in rats stably self-administering nicotine on an FR5 schedule of reinforcement (n=12, 0 mg kg⁻¹ galantamine; n=13, 0.5 mg kg⁻¹ galantamine; n=12, 5.0 mg kg⁻¹ galantamine). *P<0.05, ^#P<0.01, ⁺P<0.001 between vehicle and 5.0 mg kg⁻¹ galantamine treatments. (c) There were no effects of repeated galantamine administration on sucrose self-administration (n=5, 0 mg kg⁻¹ galantamine; n=5, 0.5 mg kg⁻¹ galantamine; n=6, 5.0 mg kg⁻¹ galantamine). FR5, fixed-ratio-5.

Figure 2

Repeated galantamine administration did not alter pica or feeding behavior in rats. No significant differences in total kaolin (a) and chow (b) consumed were noted between rats treated with vehicle (n=9), 0.5 mg kg⁻¹ galantamine (n=8) or 5.0 mg kg⁻¹ galantamine (n=9) for 10 consecutive days. Total change in body weight was also unaffected by repeated galantamine administration compared with controls (c).

Figure 3

Repeated administration of donepezil dose-dependently attenuated nicotine, but not sucrose, self-administration in rats. Total active lever responses (a) and total nicotine infusions (b) are shown for rats pretreated with vehicle (n=11), 0.1 mg kg⁻¹ donepezil (n=11), 1.0 mg kg⁻¹ donepezil (n=12) or 3.0 mg kg⁻¹ donepezil (n=10) before daily nicotine self-administration sessions. On day 1, total active lever responses and total nicotine infusions were significantly decreased in rats pretreated with 1.0 or 3.0 mg kg⁻¹ donepezil compared with vehicle-treated controls (*P<0.05, ^#P<0.01). On days 2–10, total active lever responses and total nicotine infusions were significantly decreased in rats pretreated with 3.0 mg kg⁻¹ donepezil compared with vehicle-treated controls (*P<0.05, ⁺P<0.001). (c) There were no effects of repeated donepezil administration on sucrose self-administration (n=8, 0 mg kg⁻¹ donepezil; n=8, 1.0 mg kg⁻¹ donepezil; n=9, 3.0 mg kg⁻¹ donepezil).

Figure 4

Repeated donepezil administration did not alter pica or feeding behavior in rats. No significant differences in total kaolin (a) and chow (b) consumed were noted between rats treated with vehicle or donepezil (n=10 per treatment) for 10 consecutive days. Total change in body weight was also unaffected by repeated donepezil administration compared with controls (c).

Figure 5

Repeated galantamine treatment in human smokers reduced smoking rate. The total number of cigarettes smoked per day was significantly reduced following 2 weeks of placebo (n=18) and galantamine (n=15) treatment when compared with baseline smoking rates. Although both groups reported smoking fewer cigarettes from baseline to week 1 (P-values <0.001), there was a greater reduction in cigarettes smoked per day in the galantamine group at week 2 when compared with placebo-treated control subjects. *P<0.001.

Figure 6

The subjective effects of smoking were significantly reduced in human smokers treated with repeated galantamine. Repeated galantamine treatment significantly reduced smoking satisfaction (a) and smoking reward (b) during weeks 1 and 2 of treatment (*P<0.001). No significant changes in smoking satisfaction and smoking reward were noted in the placebo group.

Figure 7

Repeated galantamine treatment in human smokers is associated with minimal adverse effects. Smokers treated with galantamine reported significantly more side effects that placebo-treated controls (*P<0.05). However, these adverse effects were rated as mild and did not preclude smokers from continuing with the treatment.