title: Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers.
abstract: Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.
authors.affiliation: Department of Psychiatry, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA. perkinska@upmc.edu
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Perkins
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.forename: Sarah
authors.initials: S
authors.lastname: Coddington
authors.forename: Christopher
authors.initials: C
authors.lastname: Jetton
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Karelitz
authors.forename: Annette
authors.initials: A
authors.lastname: Wilson
authors.forename: J Richard
authors.initials: JR
authors.lastname: Jennings
authors.forename: Robert
authors.initials: R
authors.lastname: Ferrell
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000339:Affect / Q000187:drug effects; D000483:Alleles; D000786:Anger / Q000187:drug effects; D001143:Arousal / Q000187:drug effects / Q000235:genetics; D002755:Choice Behavior / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D018598:Minisatellite Repeats / Q000235:genetics*; D009042:Motivation; D009538:Nicotine / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050638:Receptors, Dopamine D4 / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D012737:Sex Factors; D014029:Tobacco Use Disorder / Q000235:genetics*; D055815:Young Adult
chemical_list: C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D050638:Receptors, Dopamine D4; D009538:Nicotine; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases; D006854:Hydrocortisone