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

R L Ashare,M R Hayes,H D Schmidt,B A Kimmey,L E Rupprecht,M E Bowers

doi:10.1038/tp.2015.209

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.

Highlights

Cigarette smoking remains the leading cause of preventable disease and death in the United States, accounting for one of every five deaths annually.[1]
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
Total active lever responses and total nicotine infusions for rats pretreated with vehicle or galantamine daily for 10 consecutive days are shown in Figures 1a and b, respectively

Summary

Introduction

Cigarette smoking remains the leading cause of preventable disease and death in the United States, accounting for one of every five deaths annually.[1]. Acetylcholinesterase inhibitors (AChEIs), which are FDA-approved for treating cognitive deficits associated with Alzheimer’s disease,[5] have recently been proposed as potential treatments for drug addiction, including nicotine dependence.[6,7] AChEIs increase extracellular levels of acetylcholine in the brain and augment cholinergic transmission through inhibition of acetylcholinesterase, a catabolic enzyme responsible for metabolizing acetylcholine in the synapse.[8,9] Recently, we showed that acute administration of the AChEIs galantamine[10] and donepezil[11] attenuated nicotine self-administration in rats These preclinical findings are provocative and suggest that AChEIs could be repurposed as pharmacotherapies for smoking cessation. The efficacy of AChEIs for smoking cessation remains to be defined in healthy, treatment-seeking smokers without comorbidities

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