Serotonin receptors as potential targets for modulation of nicotine use and dependence.
ABSTRACT Nicotine use carries considerable health risks and plays a major role in a variety of diseases. Current pharmacological treatments to aid in smoking cessation include nicotine-replacement therapy and non-nicotinic strategies such as bupropion and varenicline. While these treatments benefit some individuals there is still a need for better and more effective treatment strategies. Nicotine is the major psychoactive substance in tobacco. Some behavioural effects of nicotine, including its reinforcing efficacy result in part from activation of mesolimbic dopamine neurons. Modulation of dopamine function is one potential treatment strategy that could treat nicotine dependence. Serotonergic neurons modulate the functioning of dopamine neurons in a complex fashion. Much of this complexity arises from the fact that serotonin (5-HT) exerts its effects through multiple receptor subtypes, some of which even act in apparent functional opposition to each other. This article reviews evidence, primarily from animal experiments, using behavioural procedures relevant to nicotine use on the potential for 5-HT receptors as targets for treating nicotine dependence. The 5-HT(1A, 2A, 2C, 3, 4, 6) receptor subtypes have received most experimental attention, with the 5-HT(1A) and 5-HT(2C) receptors being the best studied. Several studies have now shown that 5-HT(1A) receptor antagonists alleviate some of the behavioural signs induced by nicotine withdrawal. Electrophysiological and neurochemical studies show that stimulation of 5-HT(2C) receptors reduces the function of the mesolimbic dopamine pathway. 5-HT(2C) receptor agonists block the stimulatory action of nicotine on midbrain dopamine function. They also reduce several behavioural effects of nicotine including its discriminative stimulus properties and reinforcing effects. Although more work remains to be done, 5-HT(2C) receptor agonists perhaps hold the most promise as potential therapies for smoking cessation.
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ABSTRACT: The arylamine N-acetyltransferases (NATs) are involved in the metabolism of a variety of different compounds that we are exposed to on a daily basis. Many drugs and chemicals found in the environment, such as those in cigarette smoke, car exhaust fumes and in foodstuffs, can be either detoxified by NATs and eliminated from the body or bioactivated to metabolites that have the potential to cause toxicity and/or cancer. NATs have been implicated in some adverse drug reactions and as risk factors for several different types of cancers. As a result, the levels of NATs in the body have important consequences with regard to an individual's susceptibility to certain drug-induced toxicities and cancers. This review focuses on recent advances in the molecular genetics of the human NATs.The Pharmacogenomics Journal 02/2002; 2(1):30-42. · 5.13 Impact Factor
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ABSTRACT: Risk of oral cancer has been associated with exposure to tobacco smoke, alcohol and with genetic predisposition. The aromatic amines and their metabolites, a class of carcinogens present in tobacco smoke, undergo metabolism (activation or detoxification) through an N- or O-acetylation pathway by the polymorphic enzymes, N-acetyltransferases (NAT)1 or NAT2. The genes that encode these enzymes, NAT1 and NAT2, have a variety of high and low activity alleles and we analyzed these genetic polymorphisms in 62 oral squamous cell carcinoma cases, and 122 healthy control subjects from Japan. NAT1 alleles tested were NAT1*3 (C1095A), NAT1*4 (functional reference allele), NAT1*10 (T1088A,C1095A), NAT1*11(9 bp deletion), NAT1*14 (G560A), NAT1*15 (C559T) and NAT1*17 (C190T). No low activity alleles (NAT1*14, NAT1*15 and NAT1*17) were observed in these Japanese subjects. We observed significantly increased risk [odds ratio 3.72; 95% confidence interval (CI) 1.56-8.90; P < 0.01] associated with the NAT1*10 allele, an allele that contains a variant polyadenylation signal. Stratifying by smoking status we found odds ratios of 5.9 (95% CI 1.13-30.6; P < 0.05) for non-smokers with the NAT1*10 allele and 3.1 (95% CI 1.09-9.07; P < 0.05) for smokers, but these risks were not significantly different from each other. Thus, we did not observe that NAT1*10 alleles confer differential risk among smokers and non-smokers. NAT2 rapid acetylation genotype was not a significant risk factor for oral cancer in this Japanese study population. This is the first study to test for oral cancer risk associated with polymorphism in the NAT1 and NAT2 genes, and these positive findings in our pilot study, while based on small numbers, suggest that the NAT1*10 allele may be a genetic determinant of oral squamous cell carcinoma among Japanese people.Carcinogenesis 10/1998; 19(10):1803-7. · 5.64 Impact Factor
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ABSTRACT: Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus and account for 6.4% of all new cancers in Europe. In the context of a multicenter case-control study conducted in 14 centers within 10 European countries and comprising 1,511 cases and 1,457 controls (ARCAGE study), 115 single nucleotide polymorphisms (SNP) from 62 a priori-selected genes were studied in relation to UADT cancer. We found 11 SNPs that were statistically associated with UADT cancers overall (5.75 expected). Considering the possibility of false-positive results, we focused on SNPs in CYP2A6, MDM2, tumor necrosis factor (TNF), and gene amplified in squamous cell carcinoma 1 (GASC1), for which low P values for trend (P trend<0.01) were observed in the main effects analyses of UADT cancer overall or by subsite. The rare variant of CYP2A6 -47A>C (rs28399433), a phase I metabolism gene, was associated with reduced UADT cancer risk (P trend=0.01). Three SNPs in the MDM2 gene, involved in cell cycle control, were associated with UADT cancer. MDM2 IVS5+1285A>G (rs3730536) showed a strong codominant effect (P trend=0.007). The rare variants of two SNPs in the TNF gene were associated with a decreased risk; for TNF IVS1+123G>A (rs1800610), the P trend was 0.007. Variants in two SNPs of GASC1 were found to be strongly associated with increased UADT cancer risk (for both, P trend=0.008). This study is the largest genetic epidemiologic study on UADT cancers in Europe. Our analysis points to potentially relevant genes in various pathways.Cancer Research 04/2009; 69(7):2956-65. · 8.65 Impact Factor