title: Naltrexone modification of drinking effects in a subacute treatment and bar-lab paradigm: influence of OPRM1 and dopamine transporter (SLC6A3) genes.
abstract: BACKGROUND
  Naltrexone is moderately effective for the treatment of alcohol dependence, but there is great individual variability. The opioid receptor (OPRM1) single nucleotide polymorphism (SNP) asn40asp has been shown to alter alcohol and naltrexone response in animals and humans. In addition, the brain opioid and dopamine systems interact and might underlie drinking and craving. This study investigated the effects of the OPRM1 SNP and dopamine transporter (DAT) variable number of tandem repeat (VNTR) genetic differences on drinking, alcohol effects, and naltrexone response under controlled conditions in nontreatment-seeking alcoholics.
  
  
  METHODS
  Two hundred and sixty-five nontreatment-seeking individuals with alcohol dependence were genotyped a priori for the OPRM1 asn40asp SNP and post hoc for DAT (SLC6A3) 9 and 10 VNTRs. Asp40 carriers (n = 43) and matched asn40 homozygotes (n = 40) were randomized to naltrexone or placebo for 7 days before receiving a priming drink and limited-access alcohol consumption in a bar-lab setting. Effects of genotypes on natural drinking as well as drinking, alcohol effects, and response to naltrexone in the bar-lab setting were examined by genotype.
  
  
  RESULTS
  There were no significant main effects of naltrexone or OPRM1 genotype, or any medication by OPRM1 interaction, on drinking variables. However, in individuals who had at least one DAT 9 VNTR, and who were also OPRM1 asn40 homozygotes, naltrexone reduced drinks/d consumed under natural conditions (p = 0.006), but not in the bar-lab. OPRM1 asn40 homozygotes (p = 0.028) and DAT 9 VNTR carriers (p = 0.032) had more stimulation to alcohol after the priming drink.
  
  
  CONCLUSIONS
  This study does not support a salient role for the OPRM1 asp40 alone in predicting drinking or naltrexone effects. However, although exploratory and in need of replication, it introduces the possibility that epistasis between the OPRM1 gene and DAT gene might need to be taken into account when examining differential genetic response to alcohol or medication treatment, especially in early-stage alcoholics.
authors.affiliation: Institute of Psychiatry, Medical University of South Carolina, 67 President St., Charleston, SC 29425, USA. antonr@musc.edu
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Anton
authors.forename: Konstantin K
authors.initials: KK
authors.lastname: Voronin
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Randall
authors.forename: Hugh
authors.initials: H
authors.lastname: Myrick
authors.forename: Abraham
authors.initials: A
authors.lastname: Tiffany
mesh_terms: D000328:Adult; D000368:Aged; D000428:Alcohol Drinking / Q000188:drug therapy / Q000235:genetics*; D000437:Alcoholism / Q000188:drug therapy / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000627:therapeutic use*; D009292:Narcotic Antagonists / Q000627:therapeutic use; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012931:Social Environment; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D009292:Narcotic Antagonists; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; C493214:SLC6A3 protein, human; D009271:Naltrexone