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.

Neuropeptide systems and new treatments for nicotine addiction

“…These drugs enhance cholinergic transmission and have received FDA approval for the treatment of Alzheimer’s disease (Birks 2006). Recent studies suggest that acetylcholinesterase inhibitors (e.g., galantamine and donepezil) attenuate the self-administration of nicotine in rodents and decrease smoking in humans (Ashare et al 2016; Hopkins et al 2012; Kimmey et al 2014). …”

Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking

“…Translational studies trialing acetylcholinesterase inhibitors (AChEIs) have yielded favorable results. For example, one group reported results in 2016 that were consistent with previous studies, suggesting reductions in nicotine reinforcement through cholinergic augmentation . Their most recent trial was designed to determine the effects of repeated administration of combination galantamine‐donepezil on voluntary nicotine taking in rats, as well as on smoking behavior in human smokers .…”

“…For example, one group reported results in 2016 that were consistent with previous studies, suggesting reductions in nicotine reinforcement through cholinergic augmentation. 86 Their most recent trial was designed to determine the effects of repeated administration of combination galantaminedonepezil on voluntary nicotine taking in rats, as well as on smoking behavior in human smokers. 86 In humans, compared with placebo, repeated galantamine treatment reduced smoking behavior, as well as smoking satisfaction and reward, and it was not associated with tolerance and/or significant adverse effects.…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…Systemic administration of the AChEIs galantamine [37] and donepezil [111] attenuates nicotine seeking in rats, suggesting that enhanced cholinergic tone is sufficient to reduce nicotine consumption and smoking relapse. The translational implications of these findings are supported by a small clinical trial showing a significant reduction in total daily cigarettes smoked and the subjective measures of smoking in cigarette smokers treated with galantamine [112]. Moreover, systemic galantamine administration improves cognitive performance in rodents and humans during nicotine withdrawal [113, 114].…”