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Norepinephrine Transporter Gene Variation Modulates Acute Response to d-Amphetamine

      Background

      Individual differences in subjective responses to stimulant drugs such as amphetamine may influence risk of abuse as well as clinical-treatment response to these drugs. Because the effects of amphetamine are mediated in part by the norepinephrine transporter (SLC6A2), we examined interindividual differences in mood response to amphetamine in relation to SLC6A2 gene polymorphisms.

      Methods

      Ninety-nine healthy volunteers participated in three sessions in which they randomly received either placebo or d-amphetamine (10 mg or 20 mg) under double-blind conditions. Every subject completed self-report measures on subjective effects (Profile of Mood States). Afterward, all individuals were genotyped for eight SLC6A2 gene polymorphisms. Individual genotypes and haplotypes were investigated.

      Results

      The intronic 36001C/C (rs47958) genotype was associated with increases in positive mood and elation after 20 mg of d-amphetamine. Positive mood and elation levels were also found to be associated with the haplotype GCC formed from 28257G/C (rs36017), 28323C/T (rs2270935), and 36001A/C (rs47958). These findings remained significant after adjustment for multiple testing.

      Conclusions

      Polymorphisms in the SLC6A2 gene were associated with mood responses to d-amphetamine. If confirmed, this observation may contribute to a better understanding of interindividual variations in the clinical response to amphetamine and in the risk of becoming addicted to amphetamine.

      Key Words

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      References

        • American Psychiatric Association
        Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Press, Washington, DC1994
        • Bacanu S.-A.
        • Devlin B.
        • Roeder K.
        The power of genomic control.
        Am J Hum Genet. 2000; 66: 1933-1944
        • Brauer L.H.
        • de Wit H.
        Subjective responses to d-amphetamine alone and after pimozide pretreatment in normal healthy volunteers.
        Biol Psychiatry. 1996; 39: 26-32
        • Brüss M.
        • Kunz J.
        • Lingen B.
        • Bönisch H.
        Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter.
        Hum Genet. 1993; 91: 278-280
        • Crabbe J.C.
        • Jarvik L.F.
        • Liston E.H.
        • Jenden D.J.
        Behavioral responses to amphetamine in identical twins.
        Acta Genet Med Gemellol (Roma). 1983; 32: 139-149
        • Cubells J.F.
        • Kim K.S.
        • Baker H.
        • Volpe B.T.
        • Chung Y.
        • Houpt T.A.
        • et al.
        Differential in vivo regulation of mRNA encoding the norepinephrine transporter and tyrosine hydroxylase in rat adrenal medulla and locus ceruleus.
        J Neurochem. 1995; 65: 502-509
        • Derogatis L.
        SCL-90-R Manual II. Clinical Psychometric Research, Towson, MD1983
        • de Wit H.
        • Clark M.
        • Brauer L.H.
        Effects of d-amphetamine in grouped versus isolated humans.
        Pharmacol Biochem Behav. 1997; 57: 333-340
        • de Wit H.
        • Enggasser J.L.
        • Richards J.B.
        Acute administration of d-amphetamine decreases impulsivity in healthy volunteers.
        Neuropsychopharmacology. 2002; 5: 813-825
        • de Wit H.
        • Uhlenhuth E.H.
        • Johanson C.E.
        Individual differences in the reinforcing and subjective effects of amphetamine and diazepam.
        Drug Alcohol Depend. 1986; 16: 341-360
        • DiFranza J.R.
        • Savageau J.A.
        • Fletcher K.
        • Ockene J.K.
        • Rigotti N.A.
        • McNeill A.D.
        • et al.
        Recollections and repercussions of the first inhaled cigarette.
        Addict Behav. 2004; 29: 261-272
        • Fergusson D.M.
        • Horwood L.J.
        • Lynskey M.T.
        • Madden P.A.
        Early reactions to cannabis predict later dependence.
        Arch Gen Psychiatry. 2003; 60: 1033-1039
        • Gabbay F.H.
        Variations in affect following amphetamine and placebo: Markers of stimulant drug preference.
        Exp Clin Psychopharmacol. 2003; 11: 91-101
        • Greenhill L.L.
        • Pliszka S.
        • Dulcan M.K.
        • Bernet W.
        • Arnold V.
        • Beitchmann J.
        • et al.
        Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults.
        J Am Acad Child Adolesc Psychiatry. 2002; 41: 26-49
        • Haertzen C.A.
        • Kocher T.R.
        • Miyasato K.
        Reinforcements from the first drug experience can predict later drug habits and/or addiction: Results with coffee, cigarettes, alcohol, barbiturates, minor and major tranquilizers, stimulants, marijuana, hallucinogens, heroin, opiates and cocaine.
        Drug Alcohol Depend. 1983; 11: 147-165
        • Hahn M.K.
        • Mazei-Robinson M.
        • Blakely R.D.
        Single nucleotide polymorphisms in the human norepinephrine transporter gene impact expression, trafficking, antidepressant interaction and protein kinase C regulation.
        Mol Pharmacol. 2005; 68: 457-466
        • Haller J.
        • Bakos N.
        • Rodriguiz R.M.
        • Caron M.G.
        • Wetsel W.C.
        • Liposits Z.
        Behavioral responses to social stress in noradrenaline transporter knockout mice: Effects on social behavior and depression.
        Brain Res Bull. 2002; 58: 279-284
        • Hohoff C.
        • McDonald J.M.
        • Baune B.T.
        • Cook E.H.
        • Deckert J.
        • de Wit H.
        Interindividual variation in anxiety response to amphetamine: Possible role for adenosine A(2A) receptor gene variants.
        Am J Med Genet B Neuropsychiatr Genet. 2005; 139: 42-44
        • Hutchison K.E.
        • Wood M.D.
        • Swift R.
        Personality factors moderate subjective and psychophysiological responses to D-amphetamine in humans.
        Exp Clin Psychopharmacol. 1999; 7: 493-501
        • Inoue K.
        • Itoh K.
        • Yoshida K.
        • Shimizu T.
        • Suzuki T.
        Positive association between T-182C polymorphism in the norepinephrine transporter gene and susceptibility to major depressive disorder in a Japanese population.
        Neuropsychobiology. 2004; 50: 301-304
        • Johanson C.E.
        • Uhlenhuth E.H.
        Drug preference and mood in humans: Diazepam.
        Psychopharmacology (Berl). 1980; 71: 269-273
        • Kim C.H.
        • Kim H.S.
        • Cubells J.F.
        • Kim K.S.
        A previously undescribed intron and extensive 5′ upstream sequence, but not Phox2a-mediated transactivation, are necessary for high level cell type-specific expression of the human norepinephrine transporter gene.
        J Biol Chem. 1999; 274: 6507-6518
        • Kimberg D.Y.
        • D‘Esposito M.
        • Farah M.J.
        Effects of bromocriptine on human subjects depend on working memory capacity.
        Neuroreport. 1997; 8: 3581-3585
        • Kirley A.
        • Lowe N.
        • Hawi Z.
        • Mullins C.
        • Daly G.
        • Waldman I.
        • et al.
        Association of the 480 bp DAT1 allele with methylphenidate response in a sample of Irish children with ADHD.
        Am J Med Genet B Neuropsychiatr Genet. 2003; 15: 50-54
        • Klimek V.
        • Stockmeier C.
        • Overholser J.
        • Meltzer H.Y.
        • Kalka S.
        • Dilley G.
        • et al.
        Reduced levels of norepinephrine transporters in the locus coeruleus in major depression.
        J Neurosci. 1997; 17: 8451-8458
        • Kuhar M.J.
        • Joyce A.
        • Dominguez G.
        Genes in drug abuse.
        Drug Alcohol Depend. 2001; 62: 157-162
        • Lambert G.
        • Johansson M.
        • Agren H.
        • Friberg P.
        Reduced brain norepinephrine and dopamine release in treatment-refractory depressive illness: Evidence in support of the catecholamine hypothesis of mood disorders.
        Arch Gen Psychiatry. 2000; 57: 787-793
        • Lee Y.J.
        • Hohoff C.
        • Domschke K.
        • Sand P.
        • Kuhlenbäumer G.
        • Schirmacher A.
        • et al.
        Norepinephrine transporter (NET) promoter and 5′-UTR polymorphisms: Association analysis in panic disorder.
        Neurosci Lett. 2005; 377: 40-43
        • Li T.
        • Chen C.K.
        • Hu X.
        • Ball D.
        • Lin S.K.
        • Chen W.
        • et al.
        Association analysis of the DRD4 and COMT genes in methamphetamine abuse.
        Am J Med Genet B Neuropsychiatr Genet. 2004; 129: 120-124
        • Lorang D.
        • Amara S.G.
        • Simerly R.B.
        Cell-type-specific expression of catecholamine transporters in the rat brain.
        J Neurosci. 1993; 14: 4903-4914
        • Lott D.C.
        • Kim S.
        • Cook Jr, E.H.
        • de Wit H.
        Dopamine transporter gene associated with diminished subjective response to amphetamine.
        Neuropsychopharmacology. 2005; 30: 602-609
        • Martin W.R.
        • Sloan J.W.
        • Sapira J.D.
        • Jasinski D.R.
        Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man.
        Clin Pharmacol Ther. 1971; 12: 245-258
        • Mattay V.S.
        • Callicott J.H.
        • Bertolino A.
        • Heaton I.
        • Frank J.A.
        • Coppola R.
        • et al.
        Effects of dextroamphetamine on cognitive performance and cortical activation.
        Neuroimage. 2000; 12: 268-275
        • Mattay V.S.
        • Goldberg T.E.
        • Fera F.
        • Hariri A.R.
        • Tessitore A.
        • Egan M.F.
        • et al.
        Catechol O-methyltransferase val158-met genotype and individual variation in brain response to amphetamine.
        Proc Natl Acad Sci U S A. 2003; 100: 6186-6191
        • McNair D.
        • Lorr M.
        • Droppleman D.L.
        Profile of Mood States. Educational and Industrial Testing Service, San Diego, CA1971
        • Meyer J.
        • Wiedemann P.
        • Okladnova O.
        • Brüss M.
        • Staab T.
        • Stöber G.
        • et al.
        Cloning and functional characterization of the human norepinephrine transporter gene promoter.
        J Neural Transm. 1998; 105: 1341-1350
        • Mitchell S.H.
        • Laurent C.L.
        • de Wit H.
        Interaction of expectancy and the pharmacological effects of D-amphetamine: Subjective effects and self-administration.
        Psychopharmacology. 1996; 125: 371-378
        • Nurnberger Jr, J.I.
        • Gershon E.S.
        • Simmons S.
        • Ebert M.
        • Kessler L.R.
        • Dibble E.D.
        • et al.
        Behavioral, biochemical and neuroendocrine responses to amphetamine in normal twins and “well-state” bipolar patients.
        Psychoneuroendocrinology. 1982; 7: 163-176
        • Pörzgen P.
        • Bönisch H.
        • Brüss M.
        Molecular cloning and organization of the coding region of the human norepinephrine transporter gene.
        Biochem Biophys Res Commun. 1995; 215: 1145-1150
        • Rohde L.A.
        • Roman T.
        • Szobot C.
        • Cunha R.D.
        • Hutz M.H.
        • Biederman J.
        Dopamine transporter gene, response to methylphenidate and cerebral blood flow in attention-deficit/hyperactivity disorder: A pilot study.
        Synapse. 2003; 48: 87-89
        • Ryu S.H.
        • Lee S.H.
        • Lee H.J.
        • Cha J.H.
        • Ham B.J.
        • Han C.S.
        • et al.
        Association between norepinephrine transporter gene polymorphism and major depression.
        Neuropsychobiology. 2004; 49: 174-177
        • Selzer M.L.
        The Michigan Alcoholism Screening Test: The quest for a new diagnostic instrument.
        Am J Psychiatry. 1971; 127: 1653-1658
        • Shannon J.R.
        • Flattem N.L.
        • Jordan J.
        • Jacob G.
        • Black B.K.
        • Biaggioni I.
        • et al.
        Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.
        N Engl J Med. 2000; 342: 541-549
        • Spencer T.J.
        • Abikoff H.B.
        • Connor D.F.
        • Biedermann J.
        • Pliszka S.R.
        • Boellner S.
        • et al.
        Efficacy and safety of mixed amphetamine salts extended release (adderall XR) in the management of oppositional defiant disorder with or without comorbid attention-deficit/hyperactivity disorder in school-aged children and adolescents: A 4-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled, forced-dose-escalation study.
        Clin Ther. 2006; 28: 402-418
        • Stahl S.M.
        Blue genes and the monoamine hypothesis of depression.
        J Clin Psychiatry. 2000; 61: 77-78
        • Stein M.A.
        • Waldman I.D.
        • Sarampote C.S.
        • Seymour K.E.
        • Robb A.S.
        • Conlon C.
        • et al.
        Dopamine transporter genotype and methylphenidate dose response in children with ADHD.
        Neuropsychopharmacology. 2005; 30: 1374-1382
        • Stephens N.
        • Donelly P.
        A comparison of bayesian methods for haplotype reconstruction from population genotype data.
        Am J Hum Genet. 2003; 73: 1162-1169
        • Stephens N.
        • Smith N.J.
        • Donelly P.
        A new statistical method for haplotype reconstruction from population data.
        Am J Hum Genet. 2001; 68: 978-989
        • Sulzer D.
        • Sonders M.S.
        • Poulsen N.W.
        • Galli A.
        Mechanisms of neurotransmitter release by amphetamines: A review.
        Prog Neurobiol. 2005; 75: 406-433
        • Veenstra-VanderWeele J.
        • Qaadir A.
        • Palmer A.A.
        • Cook Jr, E.H.
        • de Wit H.
        Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine.
        Neuropsychopharmacology. 2006; 31: 1056-1063
        • White T.L.
        • Justice A.J.
        • de Wit H.
        Differential subjective effects of D-amphetamine by gender, hormone levels and menstrual cycle phase.
        Pharmacol Biochem Behav. 2002; 73: 729-741
        • Wilens T.E.
        • Biederman J.
        • Spencer T.J.
        Attention deficit/hyperactivity disorder across the lifespan.
        Annu Rev Med. 2002; 53: 113-131
        • Xu F.
        • Gainetdinov R.R.
        • Wetsel W.C.
        • Jones S.R.
        • Bohn L.M.
        • Miller G.W.
        • et al.
        Mice lacking the norepinephrine transporter are supersensitive to psychostimulants.
        Nat Neurosci. 2000; 3: 465-471