title: A prospective study of genetic factors, human laboratory phenotypes, and heavy drinking in late adolescence.
abstract: Subjective responses to alcohol are considered candidate endophenotypes for alcohol use disorder and appear to anticipate future consumption. However, prospective studies have been rare, and laboratory research has typically examined subjective responses absent measures of self-administration. This study examined the association of subjective responses with subsequent laboratory self-administration, also evaluating laboratory phenotypes in relation to putative genetic risk factors [family history (FH) of alcohol dependence and OPRM1 genotype] and subsequent heavy drinking. Participants (N = 61, M = 19.89 years, SD = 0.86) completed laboratory sessions involving intravenous alcohol challenge (Session 1) and free-access intravenous self-administration (Session 2), followed by prospective assessments. Multilevel modeling showed that higher reported stimulation and lower sedation during Session 1 independently predicted greater alcohol self-administration during Session 2. Although self-administration did not differ by FH group, participants with the OPRM1 118G allele evidenced steeper breath alcohol concentration (BrAC) trajectories and greater peak BrAC relative to 118A homozygous participants. Prospective analyses supported significant indirect associations between Session 1 subjective responses and 6-month heavy drinking via peak BrAC in Session 2. Additionally, significant indirect associations of FH (via Session 1 stimulation and Session 2 peak BrAC) and OPRM1 (via peak BrAC) with follow-up heavy drinking were observed. These results further support the utility of human laboratory phenotypes in prospective studies of alcohol use disorder risk and highlight the potential role of self-administration phenotypes in longitudinal research.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.|Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Hendershot
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Wardell
authors.affiliation: Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: McPhee
authors.affiliation: Section on Human Psychopharmacology, Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Vijay A
authors.initials: VA
authors.lastname: Ramchandani
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000294:Adolescent Behavior; D000428:Alcohol Drinking / Q000235:genetics*; D000437:Alcoholism / Q000235:genetics; D001944:Breath Tests; D058068:Endophenotypes; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D055361:Multilevel Analysis; D011446:Prospective Studies; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012646:Self Administration; D000066608:Underage Drinking; D055815:Young Adult
chemical_list: C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu
keywords: Alcohol administration; Asn40Asp; alcohol clamp; development; opioid receptor; rs1799971