48 A functional polymorphism in the promoter region of monoamine oxidase A gene (MAOA) resulting in a low expressing genotype has been found to interact with childhood sexual abuse to increase risk of alcoholism, and especially antisocial personality disorder (ASPD) occurring in the context of Alcohol Use Disorders in women.49 Other environmental factors influencing vulnerability include price, availability, early life stress exposures, and underage drinking.50 For example, alcohol prohibition from

1920 to 1933 in the US led to a large decrease in alcoholism and associated cirrhosis. Also, onset of drinking in the early adolescent Inhibitors,research,lifescience,medical or préadolescent years is a strong risk factor. However, the interactions of such factors with gene effects are even less well understood. The pharmacogenetics of pharmacotherapy Inhibitors,research,lifescience,medical Treatment of addiction encompasses two main phases: acute detoxification and maintenance. Maintenance treatment is aimed at maintaining abstinence, or harm reduction. Supportive therapy plays a vital role and this may include cognitive therapy and self-help groups. Categories of pharmacotherapeutics include: Detoxification (eg, benzodiazepines in alcoholism and clonidine in opiate withdrawal ) Agonist (eg, methadone, levo-alpha-acetyl-methadol(LAAM]) Partial agonist (eg, buprenorphine for opioid addiction) Antagonist (eg, naltrexone Inhibitors,research,lifescience,medical in alcoholism) check details Anticraving (eg,

bupropion and homotaurine in alcoholism) Aversive (eg, disulfiram). Because each of these drugs targets specific proteins and small molecules, there is considerable potential for specific pharmacogenetics of treatment response. Each of these drugs is also subject to metabolism, leading to a role for pharmacogenetic variation such as the cytochrome p450 2,6 which predicted response to bupropion in nicotine

Inhibitors,research,lifescience,medical dependence.51 The OPRM1 Asn40Asp polymorphism has, Inhibitors,research,lifescience,medical in addition to its disease associations, also been associated with naltrexone treatment response in alcoholism and as recently replicated in a large clinical trial, the COMBINE study.52 The role of OPRM1 in smoking has been studied in relation to nicotine replacement therapy. Nicotine increases the release of β-endorphins indirectly releasing dopamine and leading to pleasurable sensations Dipeptidyl peptidase associated with smoking, as shown by several studies both in rats and humans. In a randomized study, 320 smokers of European ancestry were treated with a nicotine transdermal patch or nasal spray over a 6-month period and 41% of Asp40 carriers remained abstinent at the end of 6 months as compared with 30% of Asn40/Asn40 homozygotes.53 However, the effect of genotype disappeared after treatment cessation. Another gene that may predict nicotine treatment response is cytochrome P450 2B6 (CYP2B6) which predicted treatment response with bupropion, which is metabolized by this enzyme. In a study of 426 smokers of European ancestry, participants with the low activity allele reported increased craving and higher relapse rate.