Behavioral phenotypes of impulsivity related to the ANKK1 gene are independent of an acute stressor

Melanie J White, C Phillip Morris, Bruce R Lawford, Ross McD Young, Melanie J White, C Phillip Morris, Bruce R Lawford, Ross McD Young

Abstract

Background: The A1 allele of the ANKK1 TaqIA polymorphism (previously reported as located in the D2 dopamine receptor (DRD2) gene) is associated with reduced DRD2 density in the striatum and with clinical disorders, particularly addiction. It was hypothesized that impulsivity represents an endophenotype underlying these associations with the TaqIA and that environmental stress would moderate the strength of the gene-behavior relationship.

Methods: TaqIA genotyping was conducted on 72 healthy young adults who were randomly allocated to either an acute psychosocial stress or relaxation induction condition. Behavioral phenotypes of impulsivity were measured using a card-sorting index of reinforcement sensitivity and computerized response inhibition and delay discounting tasks.

Results: Separate analyses of variance revealed associations between the A1 allele and two laboratory measures of impulsivity. The presence of the TaqIA allele (A1+) was associated with slower card-sorting in the presence of small financial reinforcers, but was overcome in a second administration after either a five-minute rest or psychosocial stress induction. A1+ participants also demonstrated significantly poorer response inhibition and faster response times on a computerized stop inhibition task, independent of acute stress exposure.

Conclusion: These findings indicate the A1 allele is associated with an endophenotype comprising both a "rash impulsive" behavioral style and reinforcement-related learning deficits. These effects are independent of stress.

Figures

Figure 1
Figure 1
Reward sensitivity (CARROT scores) pre- and post-induction (rest vs. stress) by ANKK1 TaqIA allelic status (A1+ vs. A1-). Error bars display ± 2 SEM.
Figure 2
Figure 2
(A) Stop inhibition (%) and (B) mean response latency on stop trials (ms) of ANKK1 TaqIA allelic groups (A1+ vs. A1-), as a function of stimulus onset asynchrony (SOA, ms) of the stop signal.

References

    1. American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders. 4. Washington, DC: American Psychiatric Press; 1994.
    1. Blum K, Braverman ER, Holder JM, Lubar JF, Monastra VJ, Miller D, Lubar JO, Chen TJH, Comings DE. Reward deficiency syndrome: a biogenetic model for the diagnosis and treatment of impulsive, addictive, and compulsive behaviors. J Psychoactive Drugs. 2000;32 Suppl:i–iv.
    1. Gray JA, McNaughton N. The Neuropsychology of Anxiety: An Enquiry into the Functions of the Septo-hippocampal System. 2. New York: Oxford University Press; 2000.
    1. Cloninger CR, Svrakic DM, Przybeck TR. A psychobiological model of temperament and character. Arch Gen Psychiatry. 1993;50:975–990.
    1. Noble EP. Addiction and its reward process through polymorphisms of the D2 dopamine receptor gene: a review. Eur Psychiatry. 2000;15:79–89. doi: 10.1016/S0924-9338(00)00208-X.
    1. Hur Y, Bouchard TJ., Jr The genetic correlation between impulsivity and sensation seeking traits. Behav Genet. 1997;27:455–463. doi: 10.1023/A:1025674417078.
    1. Heath AC, Cloninger CR, Martin NG. Testing a model for the genetic structure of personality: a comparison of the personality systems of Cloninger and Eysenck. J Pers Soc Psychol. 1994;66:762–775. doi: 10.1037/0022-3514.66.4.762.
    1. Eysenck HJ. A biometrical-genetical analysis of impulsive and sensation seeking behaviour. In: Zuckerman M, editor. Biological bases of sensation seeking, impulsivity and anxiety. New Jersey: Erlbaum; 1983. pp. 1–27.
    1. Neville MJ, Johnstone EC, Walton RT. Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1. Hum Mutat. 2004;23:540–545. doi: 10.1002/humu.20039.
    1. Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ. Allelic association of the D2 dopamine receptor gene with receptor binding characteristics in alcoholism. Arch Gen Psychiatry. 1991;48:648–654.
    1. Thompson J, Thomas N, Singleton A, Piggott M, Lloyd S, Perry EK, Morris CM, Perry RH, Ferrier IN, Court JA. D2 dopamine receptor gene (DRD2) TaqI A polymorphism: reduced dopamine D2 receptor binding in the human striatum associated with the A1 allele. Pharmacogenetics. 1997;7:479–484. doi: 10.1097/00008571-199712000-00006.
    1. Pohjalainen T, Rinne JO, Nagren K, Lehikoinen P, Anttila K, Syvalahti EKG, Hietala J. The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers. Mol Psychiatry. 1998;3:256–260. doi: 10.1038/sj.mp.4000350.
    1. Jonsson EG, Nothen MM, Grunhage F, Farde L, Nakashima Y, Propping P, Sedvall GC. Polymorphisms in the dopamine D2 receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Mol Psychiatry. 1999;4:290–296. doi: 10.1038/sj.mp.4000532.
    1. Noble EP. D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet. 2003;116:103–125. doi: 10.1002/ajmg.b.10005.
    1. Bobb AJ, Castellanos FX, Addington AM, Rapoport JL. Molecular genetic studies of ADHD: 1991 to 2004. Am J Med Genet. 2006;141:551–565. doi: 10.1002/ajmg.b.30086.
    1. Sery O, Drtilkova I, Theiner P, Pitelova R, Staif R, Znojil V, Lochman J, Didden W. Polymorphism of DRD2 gene and ADHD. Neuro Endocrinol Lett. 2006;27:236–240.
    1. Barr CL, Kidd KK. Population frequencies of the A1 allele at the dopamine D2 receptor locus. Biol Psychiatry. 1993;34:204–209. doi: 10.1016/0006-3223(93)90073-M.
    1. Young RM, Lawford BR, Nutting A, Noble EP. Advances in molecular genetics and the prevention and treatment of substance misuse: implications of association studies of the A1 allele of the D2 dopamine receptor gene. Addict Behav. 2004;29:1275–1294. doi: 10.1016/j.addbeh.2004.06.012.
    1. Dalley JW, Fryer TD, Brichard L, Robinson ESJ, Theobald DEH, Laane K, Pena Y, Murphy ER, Shah Y, Probst K, Abakumova I, Aigbirhio FI, Richards HK, Hong Y, Baron J-C, Everitt BJ, Robbins TW. Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. Science. 2007;315:1267–1270. doi: 10.1126/science.1137073.
    1. Caspi A, Moffitt TE. Gene-environment interactions in psychiatry: joining forces with neuroscience. Nature Rev Neurosci. 2006;7:583–590. doi: 10.1038/nrn1925.
    1. Young RM, Lawford BR, Noble EP, Kann B, Wilkie A, Ritchie T, Arnold L, Shadforth S. Harmful drinking in military veterans with post-traumatic stress disorder: association with the D2 dopamine receptor A1 allele. Alcohol Alcohol. 2002;37:451–456.
    1. Berman SM, Noble EP. The D2 dopamine receptor (DRD2) gene and family stress: interactive effects on cognitive functions in children. Behav Genet. 1997;27:33–43. doi: 10.1023/A:1025611208475.
    1. Bau CH, Almeida S, Hutz MH. The TaqI A1 allele of the dopamine D2 receptor gene and alcoholism in Brazil: association and interaction with stress and harm avoidance on severity prediction. Am J Med Genet. 2000;96:302–306. doi: 10.1002/1096-8628(20000612)96:3<302::AID-AJMG13>;2-I.
    1. Madrid GA, MacMurray J, Lee JW, Anderson BA, Comings DE. Stress as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism. Alcohol. 2001;23:117–122. doi: 10.1016/S0741-8329(00)00138-5.
    1. Erblich J, Lerman C, Self DW, Diaz GA, Bovbjerg DH. Stress-induced cigarette craving: effects of the DRD2 TaqI RFLP and SLC6A3 VNTR polymorphisms. Pharmacogenomics J. 2004;4:102–109. doi: 10.1038/sj.tpj.6500227.
    1. Bogdan R, Pizzagalli DA. Acute stress reduces reward responsiveness: implications for depression. Biol Psychiatry. 2006;60:1147–1154. doi: 10.1016/j.biopsych.2006.03.037.
    1. Conner KR, Phillips MR, Meldrum S, Knox KL, Zhang Y, Yang G. Low-planned suicides in China. Psychol Med. 2005;35:1197–204. doi: 10.1017/S003329170500454X.
    1. Roberti JW. Sensation seeking characteristics and neuroendocrine responses to an acute psychological challenge for undergraduates with career interests in forensic sciences. Internet J Forensic Sci. 2003;1:1–22.
    1. Pruessner JC, Champagne F, Meaney MJ, Dagher A. Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J Neurosci. 2004;24:2825–2831. doi: 10.1523/JNEUROSCI.3422-03.2004.
    1. Soliman A, O'Driscoll GA, Pruessner J, Holahan ALV, Boileau I, Gagnon D, Dagher A. Stress-induced dopamine release in humans at risk of psychosis: a [C-11]raclopride PET study. Neuropsychopharmacology. 2008;33:2033–2041. doi: 10.1038/sj.npp.1301597.
    1. Dougherty DM, Mathias CW, Marsh DM, Jagar AA. Laboratory behavioral measures of impulsivity. Behav Res Methods. 2005;37:82–90.
    1. Dom G, De Wilde B, Hulstijn W, Sabbe B. Dimensions of impulsive behaviour in abstinent alcoholics. Pers Indiv Diff. 2007;42:465–476. doi: 10.1016/j.paid.2006.08.007.
    1. Hariri AR, Brown SM, Williamson DE, Flory JD, de Wit H, Manuck SB. Preference for immediate over delayed rewards is associated with magnitude of ventral striatal activity. J Neurosci. 2006;26:13213–13217. doi: 10.1523/JNEUROSCI.3446-06.2006.
    1. Horn NR, Dolan M, Elliott R, Deakin JFW, Woodruff PWR. Response inhibition and impulsivity: an fMRI study. Neuropsychologia. 2003;41:1959–1966. doi: 10.1016/S0028-3932(03)00077-0.
    1. Spreen O, Strauss E. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. 2. New York: Oxford University Press; 1998.
    1. Goldberg D, Williams P. A User's Guide to the General Health Questionnaire. Berkshire: NFER-NELSON Publishing; 1988.
    1. Kirschbaum C, Pirke KM, Hellhammer DH. The Trier Social Stress Test: a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81. doi: 10.1159/000119004.
    1. Feldman PJ, Cohen S, Hamrick N, Lepore SJ. Psychological stress, appraisal, emotion and cardiovascular response in a public speaking task. Psychol Health. 2004;19:353–368. doi: 10.1080/0887044042000193497.
    1. Elsenbruch S, Lucas A, Holtmann G, Haag S, Gerken G, Riemenschneider N, Langhorst J, Kavelaars A, Heijnen CJ, Schedlowski M. Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome. Am J Gastroenterol. 2006;101:2300–2307. doi: 10.1111/j.1572-0241.2006.00837.x.
    1. Thorsteinsson EB, James JE. A meta-analysis of the effects of experimental manipulations of social support during laboratory stress. Psychol Health. 1999;14:869–886. doi: 10.1080/08870449908407353.
    1. Levenson RW. Alcohol and stress response dampening: pharmacological effects, expectancy, and tension reduction. J Abn Psychol. 1980;89:528–538. doi: 10.1037/0021-843X.89.4.528.
    1. Steele CM, Josephs RA. Drinking your troubles away II: an attention-allocation model of alcohol's effect on psychological stress. J Abn Psychol. 1988;97:196–205. doi: 10.1037/0021-843X.97.2.196.
    1. Preston SD, Tansfield RBS, Buchanan TW, Bechara A. Effects of anticipatory stress on decision making in a gambling task. Behav Neurosci. 2007;121:257–263. doi: 10.1037/0735-7044.121.2.257.
    1. Powell J, Al-Adawi S, Morgan J, Greenwood RJ. Motivational deficits after brain injury: effects of bromocriptine in 11 patients. J Neurol Neurosurg Psychiatry. 1996;60:416–421. doi: 10.1136/jnnp.60.4.416.
    1. Kambouropoulos N, Staiger PK. Personality and responses to appetitive and aversive stimuli: the joint influence of behavioural approach and behavioural inhibition systems. Pers Indiv Diff. 2004;37:1153–1165. doi: 10.1016/j.paid.2003.11.019.
    1. Speilberger CD. State-Trait Anxiety Inventory for Adults (Form Y): Sampler Set. Redwood City, California: Mind Garden; 1983.
    1. Grandy DK, Zhang Y, Civelli O. PCR detection of the TaqA RFLP at the DRD2 locus. Hum Mol Genet. 1993;2:2197. doi: 10.1093/hmg/2.12.2197-a.
    1. Kirsch P, Reuter M, Mier D, Lonsdorf T, Stark R, Gallhofer B, Vaitl D, Hennig J. Imaging gene-substance interactions: the effect of the DRD2 TaqIA polymorphism and the dopamine agonist bromocriptine on the brain activation during the anticipation of reward. Neurosci Lett. 2006;405:196–201. doi: 10.1016/j.neulet.2006.07.030.
    1. Rodriguez-Jimenez R, Ãvila C, Ponce G, Ibanez MI, Rubio G, Jimenez-Arriero MA, Ampuero I, Ramos JA, Hoenicka J, Palomo T. The TaqIA polymorphism linked to the DRD2 gene is related to lower attention and less inhibitory control in alcoholic patients. Eur Psychiatry. 2006;21:66–69. doi: 10.1016/j.eurpsy.2005.05.010.
    1. Bekker EM, Overtoom CC, Kenemans JL, Kooij JJ, De Noord I, Buitelaar JK, Verbaten MN. Stopping and changing in adults with ADHD. Psychol Med. 2005;35:807–816. doi: 10.1017/S0033291704003459.
    1. Eisenberg DT, Mackillop J, Modi M, Beauchemin J, Dang D, Lisman SA, Lum JK, Wilson DS. Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study. Behav Brain Funct. 2007;3:2. doi: 10.1186/1744-9081-3-2.

Source: PubMed

3
订阅