Abstract
Despite what is often believed, the majority of those who experiment with substances with a dependence potential do not develop dependence. However, there is a subpopulation of users that easily becomes dependent on substances, and these individuals exhibit pre-existing comorbid traits, including novelty seeking and antisocial behavior. There appears to be a genetic basis for the susceptibility to dependence and these comorbid traits. Animal studies have identified specific genes that can alter susceptibility to dependence and response to novelty. The mechanisms underlying the genetic susceptibility to dependence and response to novelty are complex, but genetic susceptibility plays a significant role in the transition from substance use to dependence and from chronic use to addiction. We discuss two models to explain how genetic variations alter dependence susceptibility. Identification of the specific genes involved in these processes would help to identify individuals that are vulnerable to dependence/addiction and to devise novel treatment strategies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. Text revision, American Psychiatric Press: Washington, DC, 2000.
Nestler EJ . Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2001; 2: 119–128.
Hyman SE, Nestler EJ . The Molecular Foundations of Psychiatry. American Psychiatry Press, Inc.: Washington, DC, 1993.
Hyman SE, Malenka RC . Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci 2001; 2: 695–703.
Anthony JC, Warner LA, Kessler RC . Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 1994; 2: 244–268.
Substance Abuse and Mental Health Services Administration (SAMHSA). Results from the 2002 National Survey on Drug Use and Health: National Findings NHSDA Series H-22, DHHS Publication No. SMA 03-3836. Office of the Applied Studies: Rockville, MD, 2003.
Pickworth WB, Fant RV, Nelson RA, Rohrer MS, Henningfield JE . Pharmacodynamic effects of new de-nicotinized cigarettes. Nicotine Tob Res 1999; 1: 357–364.
Shahan TA, Bickel WK, Madden GJ, Badger GJ . Comparing the reinforcing efficacy of nicotine-containing and de-nicotinized cigarettes: a behavioral economic analysis. Psychopharmacology (Berl) 1999; 147: 210–216.
Barker D . Reasons for tobacco use and symptoms of nicotine withdrawal among adolescent and young adult tobacco users—United States, 1993. MMWR Morb Mortal Wkly Rep 1994; 43: 745–750.
DiFranza JR, Rigotti NA, McNeill AD, Ockene JK, Savageau JA, St Cyr D et al. Initial symptoms of nicotine dependence in adolescents. Tob Control 2000; 9: 313–319.
Keuthen NJ, Niaura RS, Borrelli B, Goldstein M, DePue J, Murphy C et al. Comorbidity, smoking behavior and treatment outcome. Psychother Psychosom 2000; 69: 244–250.
Owen N, Kent P, Wakefield M, Roberts L . Low-rate smokers. Prev Med 1995; 24: 80–84.
Shiffman S . Tobacco ‘chippers’—individual differences in tobacco dependence. Psychopharmacology (Berl) 1989; 97: 539–547.
Shiffman S, Kassel JD, Paty J, Gnys M, Zettler-Segal M . Smoking typology profiles of chippers and regular smokers. J Subst Abuse 1994; 6: 21–35.
Shiffman S, Paty JA, Gnys M, Kassel JD, Elash C . Nicotine withdrawal in chippers and regular smokers: subjective and cognitive effects. Health Psychol 1995; 14: 301–309.
Shiffman S, Paty J, Kassel JD, Gnys M, Zettler-Segal M . Smoking behavior and smoking history of tobacco chippers. Exp Clin Psychopharm 1994; 2: 126–142.
Shiffman S, Fischer LB, Zettler-Segal M, Benowitz NL . Nicotine exposure among nondependent smokers. Arch Gen Psychiatry 1990; 47: 333–336.
Shiffman S, Zettler-Segal M, Kassel J, Paty J, Benowitz NL, O'Brien G . Nicotine elimination and tolerance in non-dependent cigarette smokers. Psychopharmacology (Berl) 1992; 109: 449–456.
Robins LN, Davis DH, Goodwin DW . Drug use by US army enlisted men in Vietnam: a follow-up on their return home. Am J Epidemiol 1974; 99: 235–249.
Robins LN, Helzer JE, Davis DH . Narcotic use in southeast Asia and afterward. An interview study of 898 Vietnam returnees. Arch Gen Psychiatry 1975; 32: 955–961.
Robins LN . Vietnam veterans' rapid recovery from heroin addiction: a fluke or normal expectation? Addiction 1993; 88: 1041–1054.
Inturrisi CE . Clinical pharmacology of opioids for pain. Clin J Pain 2002; 18: S3–S13.
Fishbain DA, Rosomoff HL, Rosomoff RS . Drug abuse, dependence, and addiction in chronic pain patients. Clin J Pain 1992; 8: 77–85.
Sproule BA, Busto UE, Somer G, Romach MK, Sellers EM . Characteristics of dependent and nondependent regular users of codeine. J Clin Psychopharmacol 1999; 19: 367–372.
Zuckerman M, Cloninger CR . Relationships between Cloninger's, Zuckerman's and Eysenck's dimensions of personality. Person Indiv Diff 1996; 21: 283–285.
Cloninger CR . Neurogenetic adaptive mechanisms in alcoholism. Science 1987; 236: 410–416.
Svrakic DM, Whitehead C, Przybeck TR, Cloninger CR . Differential diagnosis of personality disorders by the seven-factor model of temperament and character. Arch Gen Psychiatry 1993; 50: 991–999.
Zuckerman M, Kuhlman DM . Personality and risk-taking: common biosocial factors. J Pers 2000; 68: 999–1029.
Perkins KA, Gerlach D, Broge M, Grobe JE, Wilson A . Greater sensitivity to subjective effects of nicotine in nonsmokers high in sensation seeking. Exp Clin Psychopharmacol 2000; 8: 462–471.
Carton S, Le Houezec J, Lagrue G, Jouvent R . Relationships between sensation seeking and emotional symptomatology during smoking cessation with nicotine patch therapy. Addict Behav 2000; 25: 653–662.
Heath AC, Madden PA, Slutske WS, Martin NG . Personality and the inheritance of smoking behavior: a genetic perspective. Behav Genet 1995; 25: 103–117.
Kassel JD, Shiffman S, Gnys M, Paty J, Zettler-Segal M . Psychosocial and personality differences in chippers and regular smokers. Addict Behav 1994; 19: 565–575.
Lipkus IM, Barefoot JC, Feaganes J, Williams RB, Siegler IC . A short MMPI scale to identify people likely to begin smoking. J Pers Assess 1994; 62: 213–222.
Masse LC, Tremblay RE . Behavior of boys in kindergarten and the onset of substance use during adolescence. Arch Gen Psychiatry 1997; 54: 62–68.
Sher KJ, Bartholow BD, Wood MD . Personality and substance use disorders: a prospective study. J Consult Clin Psychol 2000; 68: 818–829.
Basiaux P, le Bon O, Dramaix M, Massat I, Souery D, Mendlewicz J et al. Temperament and Character Inventory (TCI): personality profile and sub-typing in alcoholic patients: a controlled study. Alcohol Alcohol 2001; 36: 584–587.
Cloninger CR, Sigvardsson S, Bohman M . Childhood personality predicts alcohol abuse in young adults. Alcohol Clin Exp Res 1988; 12: 494–505.
Hallman J, von Knorring L, Oreland L . Personality disorders according to DSM-III-R and thrombocyte monoamine oxidase activity in type 1 and type 2 alcoholics. J Stud Alcohol 1996; 57: 155–161.
Sigvardsson S, Bohman M, Cloninger CR . Replication of the Stockholm Adoption Study of alcoholism. Confirmatory cross-fostering analysis. Arch Gen Psychiatry 1996; 53: 681–687.
Finn PR, Mazas CA, Justus AN, Steinmetz J . Early-onset alcoholism with conduct disorder: go/no go learning deficits, working memory capacity, and personality. Alcohol Clin Exp Res 2002; 26: 186–206.
Lynskey MT, Fergusson DM, Horwood LJ . The origins of the correlations between tobacco, alcohol, and cannabis use during adolescence. J Child Psychol Psychiatry 1998; 39: 995–1005.
Mabry EA, Khavari KA . Attitude and personality correlates of hallucinogenic drug use. Int J Addict 1986; 21: 691–699.
Wills TA, Vaccaro D, McNamara G . Novelty seeking, risk taking, and related constructs as predictors of adolescent substance use: an application of Cloninger's theory. J Subst Abuse 1994; 6: 1–20.
Conway KP, Kane RJ, Ball SA, Poling JC, Rounsaville BJ . Personality, substance of choice, and polysubstance involvement among substance dependent patients. Drug Alcohol Depend 2003; 71: 65–75.
Barry KL, Fleming MF, Manwell LB, Copeland LA . Conduct disorder and antisocial personality in adult primary care patients. J Fam Pract 1997; 45: 151–158.
Boyle MH, Offord DR . Psychiatric disorder and substance use in adolescence. Can J Psychiatry 1991; 36: 699–705.
Rohde P, Kahler CW, Lewinsohn PM, Brown RA . Psychiatric disorders, familial factors, and cigarette smoking: II. Associations with progression to daily smoking. Nicotine Tob Res 2004; 6: 119–132.
Rohde P, Kahler CW, Lewinsohn PM, Brown RA . Psychiatric disorders, familial factors, and cigarette smoking: III. Associations with cessation by young adulthood among daily smokers. Nicotine Tob Res 2004; 6: 509–522.
Serman N, Johnson JG, Geller PA, Kanost RE, Zacharapoulou H . Personality disorders associated with substance use among American and Greek adolescents. Adolescence 2002; 37: 841–854.
Finn PR, Sharkansky EJ, Brandt KM, Turcotte N . The effects of familial risk, personality, and expectancies on alcohol use and abuse. J Abnorm Psychol 2000; 109: 122–133.
Tomasson K, Vaglum P . A nationwide representative sample of treatment-seeking alcoholics: a study of psychiatric comorbidity. Acta Psychiatr Scand 1995; 92: 378–385.
Brown SA, Gleghorn A, Schuckit MA, Myers MG, Mott MA . Conduct disorder among adolescent alcohol and drug abusers. J Stud Alcohol 1996; 57: 314–324.
Carbonneau R, Tremblay RE, Vitaro F, Dobkin PL, Saucier JF, Pihl RO . Paternal alcoholism, paternal absence and the development of problem behaviors in boys from age six to twelve years. J Stud Alcohol 1998; 59: 387–398.
Hawkins JD, Catalano RF, Miller JY . Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: implications for substance abuse prevention. Psychol Bull 1992; 112: 64–105.
Lynskey MT, Fergusson DM . Childhood conduct problems, attention deficit behaviors, and adolescent alcohol, tobacco, and illicit drug use. J Abnorm Child Psychol 1995; 23: 281–302.
Windle M . A longitudinal study of antisocial behaviors in early adolescence as predictors of late adolescent substance use: gender and ethnic group differences. J Abnorm Psychol 1990; 99: 86–91.
Young SE, Mikulich SK, Goodwin MB, Hardy J, Martin CL, Zoccolillo MS et al. Treated delinquent boys' substance use: onset, pattern, relationship to conduct and mood disorders. Drug Alcohol Depend 1995; 37: 149–162.
Feingold A, Ball SA, Kranzler HR, Rounsaville BJ . Generalizability of the type A/type B distinction across different psychoactive substances. Am J Drug Alcohol Abuse 1996; 22: 449–462.
Rounsaville BJ, Anton SF, Carroll K, Budde D, Prusoff BA, Gawin F . Psychiatric diagnoses of treatment-seeking cocaine abusers. Arch Gen Psychiatry 1991; 48: 43–51.
Sullivan PF, Kendler KS . The genetic epidemiology of smoking. Nicotine Tob Res 1999; 1(Suppl 2): S51–S57.
Pickens RW, Svikis DS, McGue M, Lykken DT, Heston LL, Clayton PJ . Heterogeneity in the inheritance of alcoholism. A study of male and female twins. Arch Gen Psychiatry 1991; 48: 19–28.
Tsuang MT, Lyons MJ, Eisen SA, Goldberg J, True W, Lin N . Genetic influences on DSM-III-R drug abuse and dependence: a study of 3372 twin pairs. Am J Med Genet 1996; 67: 473–477.
Kendler KS, Thornton LM, Pedersen NL . Tobacco consumption in Swedish twins reared apart and reared together. Arch Gen Psychiatry 2000; 57: 886–892.
Arinami T, Ishiguro H, Onaivi ES . Polymorphisms in genes involved in neurotransmission in relation to smoking. Eur J Pharmacol 2000; 410: 215–226.
Enoch MA . Pharmacogenomics of alcohol response and addiction. Am J Pharmacogenomics 2003; 3: 217–232.
Kreek MJ, Nielsen DA, LaForge KS . Genes associated with addiction: alcoholism, opiate, and cocaine addiction. Neuromolecular Med 2004; 5: 85–108.
Lerman C, Niaura R . Applying genetic approaches to the treatment of nicotine dependence. Oncogene 2002; 21: 7412–7420.
Uhl GR, Liu QR, Naiman D . Substance abuse vulnerability loci: converging genome scanning data. Trends Genet 2002; 18: 420–425.
Walton R, Johnstone E, Munafo M, Neville M, Griffiths S . Genetic clues to the molecular basis of tobacco addiction and progress towards personalized therapy. Trends Mol Med 2001; 7: 70–76.
Deroche-Gamonet V, Belin D, Piazza PV . Evidence for addiction-like behavior in the rat. Science 2004; 305: 1014–1017.
Bardo MT, Donohew RL, Harrington NG . Psychobiology of novelty seeking and drug seeking behavior. Behav Brain Res 1996; 77: 23–43.
Klebaur JE, Bevins RA, Segar TM, Bardo MT . Individual differences in behavioral responses to novelty and amphetamine self-administration in male and female rats. Behav Pharmacol 2001; 12: 267–275.
Orsini C, Buchini F, Piazza PV, Puglisi-Allegra S, Cabib S . Susceptibility to amphetamine-induced place preference is predicted by locomotor response to novelty and amphetamine in the mouse. Psychopharmacology (Berl) 2004; 172: 264–270.
Piazza PV, Deminiere JM, Le Moal M, Simon H . Factors that predict individual vulnerability to amphetamine self-administration. Science 1989; 245: 1511–1513.
DeFries JC, Gervais MC, Thomas EA . Response to 30 generations of selection for open-field activity in laboratory mice. Behav Genet 1978; 8: 3–13.
Crabbe JC . Genetic contributions to addiction. Annu Rev Psychol 2002; 53: 435–462.
Laakso A, Mohn AR, Gainetdinov RR, Caron MG . Experimental genetic approaches to addiction. Neuron 2002; 36: 213–228.
Chao J, Nestler EJ . Molecular neurobiology of drug addiction. Annu Rev Med 2004; 55: 113–132.
Hiroi N, Brown JR, Haile CN, Ye H, Greenberg ME, Nestler EJ . FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. Proc Natl Acad Sci USA 1997; 94: 10397–10402.
Hiroi N, Marek GJ, Brown JR, Ye H, Saudou F, Vaidya VA et al. Essential role of the fosB gene in molecular, cellular, and behavioral actions of chronic electroconvulsive seizures. J Neurosci 1998; 18: 6952–6962.
Kelz MB, Chen J, Carlezon Jr WA, Whisler K, Gilden L, Beckmann AM et al. Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine. Nature 1999; 401: 272–276.
Chen J, Zhang Y, Kelz MB, Steffen C, Ang ES, Zeng L et al. Induction of cyclin-dependent kinase 5 in the hippocampus by chronic electroconvulsive seizures: role of [Delta]FosB. J Neurosci 2000; 20: 8965–8971.
Malleret G, Hen R, Guillou JL, Segu L, Buhot MC . 5-HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze. J Neurosci 1999; 19: 6157–6168.
Rocha BA, Scearce-Levie K, Lucas JJ, Hiroi N, Castanon N, Crabbe JC et al. Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor. Nature 1998; 393: 175–178.
Cardinal RN, Pennicott DR, Sugathapala CL, Robbins TW, Everitt BJ . Impulsive choice induced in rats by lesions of the nucleus accumbens core. Science 2001; 292: 2499–2501.
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG . Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996; 379: 606–612.
Rocha BA, Fumagalli F, Gainetdinov RR, Jones SR, Ator R, Giros B et al. Cocaine self-administration in dopamine-transporter knockout mice. Nat Neurosci 1998; 1: 132–137.
Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R et al. Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc Natl Acad Sci USA 1998; 95: 7699–7704.
Dulawa SC, Grandy DK, Low MJ, Paulus MP, Geyer MA . Dopamine D4 receptor-knock-out mice exhibit reduced exploration of novel stimuli. J Neurosci 1999; 19: 9550–9556.
Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G et al. Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 1997; 90: 991–1001.
Xu F, Gainetdinov RR, Wetsel WC, Jones SR, Bohn LM, Miller GW et al. Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci 2000; 3: 465–471.
Lee M, Chen K, Shih JC, Hiroi N . MAO-B knockout mice exhibit deficient habituation of locomotor activity but normal nicotine intake. Genes Brain Behav 2004; 3: 216–227.
Sora I, Hall FS, Andrews AM, Itokawa M, Li XF, Wei HB et al. Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc Natl Acad Sci USA 2001; 98: 5300–5305.
Messer CJ, Eisch AJ, Carlezon Jr WA, Whisler K, Shen L, Wolf DH et al. Role for GDNF in biochemical and behavioral adaptations to drugs of abuse. Neuron 2000; 26: 247–257.
Haile CN, Hiroi N, Nestler EJ, Kosten TA . Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats. Synapse 2001; 41: 179–190.
Kabbaj M, Yoshida S, Numachi Y, Matsuoka H, Devine DP, Sato M . Methamphetamine differentially regulates hippocampal glucocorticoid and mineralocorticoid receptor mRNAs in Fischer and Lewis rats. Mol Brain Res 2003; 117: 8–14.
Werme M, Olson L, Brene S . NGFI-B and nor1 mRNAs are upregulated in brain reward pathways by drugs of abuse: different effects in Fischer and Lewis rats. Mol Brain Res 2000; 76: 18–24.
Werme M, Thoren P, Olson L, Brene S . Running and cocaine both upregulate dynorphin mRNA in medial caudate putamen. Eur J Neurosci 2000; 12: 2967–2974.
Hurd YL, Svensson P, Ponten M . The role of dopamine, dynorphin, and CART systems in the ventral striatum and amygdala in cocaine abuse. Ann NY Acad Sci 1999; 877: 499–506.
Staley JK, Mash DC . Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities. J Neurosci 1996; 16: 6100–6106.
Tang WX, Fasulo WH, Mash DC, Hemby SE . Molecular profiling of midbrain dopamine regions in cocaine overdose victims. J Neurochem 2003; 85: 911–924.
White NM . Addictive drugs as reinforcers: multiple partial actions on memory systems. Addiction 1996; 91: 921–949.
Acknowledgements
This work was supported by the NIDA (R01DA13232) and by funds from the Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine (Dr T Byram Karasu and Dr Donald Faber); by funds from the Program in Human Genetics/Howard Hughes Funds, Albert Einstein College of Medicine to NH; and by funds from the Albert Einstein College of Medicine/Montefiore Medical Center to SA. This article is dedicated to T Klein.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hiroi, N., Agatsuma, S. Genetic susceptibility to substance dependence. Mol Psychiatry 10, 336–344 (2005). https://doi.org/10.1038/sj.mp.4001622
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001622
Keywords
This article is cited by
-
Relation of parenting child abuse based on attachment styles, parenting styles, and parental addictions
Current Psychology (2023)
-
Distinct motivations to seek out information in healthy individuals and problem gamblers
Translational Psychiatry (2021)
-
Alcohol and nicotine codependence-associated DNA methylation changes in promoter regions of addiction-related genes
Scientific Reports (2017)
-
Novelty Seeking and Drug Addiction in Humans and Animals: From Behavior to Molecules
Journal of Neuroimmune Pharmacology (2016)
-
Haplotype-based study of the association of alcohol and acetaldehyde-metabolising genes with alcohol dependence (with or without comorbid anxiety symptoms) in a Cape Mixed Ancestry population
Metabolic Brain Disease (2014)