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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.

SUBMITTER: Ashare RL

PROVIDER: S-EPMC5068882 | biostudies-other | 2016 Jan

REPOSITORIES: biostudies-other

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

Ashare R L RL Kimmey B A BA Rupprecht L E LE Bowers M E ME Hayes M R MR Schmidt H D HD

Translational psychiatry 20160119

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 u ...[more]

PMID: 26784967

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Project description:Tobacco cigarette smoking, with nicotine (NIC) as the addictive component, is a large risk factor for human mortality. In animals, repeated NIC exposure leads to sensitization (SST) and enhances self-administration (SA) of NIC. However, the molecular basis of SST and SA and their genetic relevance to smoking behavior are poorly understood. Using F1 progeny of inbred Envigo rats (F344/BN), we carried out a transcriptional profiling of NIC SST and SA in ventral tegmental area (VTA), nucleus accumbens core (Nac) and shell (Nash). We observed male-specific NIC SST and a parental effect of NIC with SA only present in paternal F344 crosses. Gene differential expression (DE) analysis revealed sex and brain region-specific transcriptomic signatures of SST and SA, with genes downregulated in male VTA associated with both SST and SA, while genes upregulated in male Nac were associated with SA. DE genes associated with SST and SA are enriched for those related to synaptic processes, myelin sheath, and tobacco use disorder or chemdependency. Interestingly, we found that for SST the downregulated genes in the male VTA tended to be upregulated in female VTA, and the overlapping genes were strongly enriched for smoking genome-wide association study (GWAS) risk variants, which may thus explain male-specific SST. To gain mechanistic insight on the observed parental effect of SA, we analyzed the allelic imbalance of expression (AIE) in reciprocally crossed F1 rats that exhibited differential tendency of SA and found widespread region-specific AIE. For the SA-inclined rats, the genes showing AIE bias towards paternal F344 alleles in Nac were strongly enriched for genes upregulated in Nac DE—the gene set most relevant to NIC SA—and also for GWAS risk variants of smoking initiation. These findings show a prominent role for sex and region-specific gene expression and imprinting in NIC SST and SA, and suggest a mechanistic link between genes underlying these processes and human NIC addiction. This study provides a resource for understanding the biology underlying the genetic findings on human smoking phenotypes.

Project description:IntroductionBecause 30% of cigarettes sold in the United States are characterized as menthol cigarettes, it is important to understand how menthol preference may affect the impact of a nicotine reduction policy.MethodsIn a recent trial, non-treatment-seeking smokers were randomly assigned to receive very low nicotine cigarettes (VLNC; 0.4 mg nicotine/g tobacco) or normal nicotine cigarettes (NNC; 15.5 mg/g) for 20 weeks. On the basis of preference, participants received menthol or non-menthol cigarettes. We conducted multivariable regression analyses to examine whether menthol preference moderated the effects of nicotine content on cigarettes per day (CPD), breath carbon monoxide (CO), urinary total nicotine equivalents (TNE), urinary 2-cyanoethylmercapturic acid (CEMA), and abstinence.ResultsAt baseline, menthol smokers (n = 346) reported smoking fewer CPD (14.9 vs. 19.2) and had lower TNE (52.8 vs. 71.6 nmol/mg) and CO (17.7 vs. 20.5 ppm) levels than non-menthol smokers (n = 406; ps < .05). At week 20, significant interactions indicated that menthol smokers had smaller treatment effects than non-menthol smokers for CPD (-6.4 vs. -9.3), TNE (ratio of geometric means, 0.22 vs. 0.10) and CEMA (ratio, 0.56 vs. 0.37; ps < .05), and trended toward a smaller treatment effect for CO (-4.5 vs. -7.3 ppm; p = .06). Odds ratios for abstinence at week 20 were 1.88 (95% confidence interval [CI] = 0.8 to 4.4) for menthol and 9.11 (95% CI = 3.3 to 25.2) for non-menthol VLNC smokers (p = .02) relative to the NNC condition.ConclusionsAlthough menthol smokers experienced reductions in smoking, toxicant exposure, and increases in quitting when using VLNC cigarettes, the magnitude of change was smaller than that observed for non-menthol smokers.ImplicationsResults of this analysis suggest that smokers of menthol cigarettes may respond to a nicotine reduction policy with smaller reductions in smoking rates and toxicant exposure than would smokers of non-menthol cigarettes.

Dataset Information

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

Publications

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

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