Genetic susceptibility to substance dependence

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.

[1]  C. Robert Cloninger,et al.  Neurogenetic adaptive mechanisms in alcoholism. , 1987, Science.

[2]  M. Greenberg,et al.  FosB mutant mice: loss of chronic cocaine induction of Fos-related proteins and heightened sensitivity to cocaine's psychomotor and rewarding effects. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. Defries,et al.  Response to 30 generations of selection for open-field activity in laboratory mice , 1978, Behavior genetics.

[4]  H. Kranzler,et al.  Generalizability of the type A/type B distinction across different psychoactive substances. , 1996, The American journal of drug and alcohol abuse.

[5]  D. Mash,et al.  Adaptive Increase in D3 Dopamine Receptors in the Brain Reward Circuits of Human Cocaine Fatalities , 1996, The Journal of Neuroscience.

[6]  T. Wills,et al.  Novelty seeking, risk taking, and related constructs as predictors of adolescent substance use: an application of Cloninger's theory. , 1994, Journal of substance abuse.

[7]  R. Catalano,et al.  Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood: implications for substance abuse prevention. , 1992, Psychological bulletin.

[8]  M. Windle.  A longitudinal study of antisocial behaviors in early adolescence as predictors of late adolescent substance use: gender and ethnic group differences. , 1990, Journal of abnormal psychology.

[9]  M. Kabbaj,et al.  Methamphetamine differentially regulates hippocampal glucocorticoid and mineralocorticoid receptor mRNAs in Fischer and Lewis rats. , 2003, Brain research. Molecular brain research.

[10]  J. Steinmetz,et al.  Early-onset alcoholism with conduct disorder: go/no go learning deficits, working memory capacity, and personality. , 2002, Alcoholism, clinical and experimental research.

[11]  R Hen,et al.  5-HT1B Receptor Knock-Out Mice Exhibit Increased Exploratory Activity and Enhanced Spatial Memory Performance in the Morris Water Maze , 1999, The Journal of Neuroscience.

[12]  M. Munafo,et al.  Genetic clues to the molecular basis of tobacco addiction and progress towards personalized therapy. , 2001, Trends in molecular medicine.

[13]  P. Thorén,et al.  Running and cocaine both upregulate dynorphin mRNA in medial caudate putamen , 2000, The European journal of neuroscience.

[14]  S. Shiffman,et al.  Nicotine elimination and tolerance in non-dependent cigarette smokers , 1992, Psychopharmacology.

[15]  K. Sher,et al.  Personality and substance use disorders: a prospective study. , 2000, Journal of consulting and clinical psychology.

[16]  Reasons for tobacco use and symptoms of nicotine withdrawal among adolescent and young adult tobacco users--United States, 1993. , 1994, MMWR. Morbidity and mortality weekly report.

[17]  N M White,et al.  Addictive drugs as reinforcers: multiple partial actions on memory systems. , 1996, Addiction.

[18]  D. Fishbain,et al.  Drug Abuse, Dependence, and Addiction in Chronic Pain Patients , 1992, The Clinical journal of pain.

[19]  M. Greenberg,et al.  Essential Role of the fosB Gene in Molecular, Cellular, and Behavioral Actions of Chronic Electroconvulsive Seizures , 1998, The Journal of Neuroscience.

[20]  E. J. Sharkansky,et al.  The effects of familial risk, personality, and expectancies on alcohol use and abuse. , 2000, Journal of abnormal psychology.

[21]  K. Khavari,et al.  Attitude and personality correlates of hallucinogenic drug use. , 1986, The International journal of the addictions.

[22]  K. Barry,et al.  Conduct disorder and antisocial personality in adult primary care patients. , 1997, The Journal of family practice.

[23]  R. Hen,et al.  Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor , 1998, Nature.

[24]  S. Hyman,et al.  The Molecular Foundations Of Psychiatry , 1993 .

[25]  P. Sullivan,et al.  The genetic epidemiology of smoking. , 1999, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[26]  C. R. Cloninger,et al.  Relationships between Cloninger's, Zuckerman's, and Eysenck's dimensions of personality. , 1996, Personality and individual differences.

[27]  C. Lerman,et al.  Applying genetic approaches to the treatment of nicotine dependence , 2002, Oncogene.

[28]  D. Fergusson,et al.  The origins of the correlations between tobacco, alcohol, and cannabis use during adolescence. , 1998, Journal of child psychology and psychiatry, and allied disciplines.

[29]  L. Robins,et al.  The sixth Thomas James Okey Memorial Lecture. Vietnam veterans' rapid recovery from heroin addiction: a fluke or normal expectation? , 1993, Addiction.

[30]  D. Murphy,et al.  Molecular mechanisms of cocaine reward: Combined dopamine and serotonin transporter knockouts eliminate cocaine place preference , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[31]  G. Madden,et al.  Comparing the reinforcing efficacy of nicotine containing and de-nicotinized cigarettes: a behavioral economic analysis , 1999, Psychopharmacology.

[32]  K. Tomasson,et al.  A nationwide representative sample of treatment‐seeking alcoholics: a study of psychiatric comorbidity , 1995, Acta psychiatrica Scandinavica.

[33]  P. Piazza,et al.  Susceptibility to amphetamine-induced place preference is predicted by locomotor response to novelty and amphetamine in the mouse , 2004, Psychopharmacology.

[34]  J. Feaganes,et al.  A short MMPI scale to identify people likely to begin smoking. , 1994, Journal of personality assessment.

[35]  N. Hiroi,et al.  Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats , 2001, Synapse.

[36]  S. Shiffman,et al.  Psychosocial and personality differences in chippers and regular smokers. , 1994, Addictive behaviors.

[37]  J. Crabbe.  Genetic contributions to addiction. , 2002, Annual review of psychology.

[38]  C. Inturrisi.  Clinical Pharmacology of Opioids for Pain , 2002, The Clinical journal of pain.

[39]  S. Shiffman,et al.  Smoking behavior and smoking history of tobacco chippers. , 1994 .

[40]  M. Kelz,et al.  Induction of Cyclin-Dependent Kinase 5 in the Hippocampus by Chronic Electroconvulsive Seizures: Role of ΔFosB , 2000, The Journal of Neuroscience.

[41]  D. Abrams,et al.  Comorbidity, Smoking Behavior and Treatment Outcome , 2000, Psychotherapy and Psychosomatics.

[42]  M. Zuckerman,et al.  Personality and risk-taking: common biosocial factors. , 2000, Journal of personality.

[43]  A. Heath,et al.  Personality and the inheritance of smoking behavior: A genetic perspective , 1995, Behavior genetics.

[44]  C. R. Cloninger,et al.  Differential diagnosis of personality disorders by the seven-factor model of temperament and character. , 1993, Archives of general psychiatry.

[45]  C. Robert Cloninger,et al.  Replication of the Stockholm Adoption Study of alcoholism. Confirmatory cross-fostering analysis. , 1996, Archives of general psychiatry.

[46]  D. Lykken,et al.  Heterogeneity in the inheritance of alcoholism. A study of male and female twins. , 1991, Archives of general psychiatry.

[47]  Fei Xu,et al.  Mice lacking the norepinephrine transporter are supersensitive to psychostimulants , 2000, Nature Neuroscience.

[48]  R. Bevins,et al.  Individual differences in behavioral responses to novelty and amphetamine self‐administration in male and female rats , 2001, Behavioural pharmacology.

[49]  J. A. Chester,et al.  Mice Lacking Dopamine D4 Receptors Are Supersensitive to Ethanol, Cocaine, and Methamphetamine , 1997, Cell.

[50]  R. Mark Wightman,et al.  Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter , 1996, Nature.

[51]  B. Prusoff,et al.  Psychiatric diagnoses of treatment-seeking cocaine abusers. , 1991, Archives of general psychiatry.

[52]  S. Shiffman,et al.  Smoking typology profiles of chippers and regular smokers. , 1994, Journal of substance abuse.

[53]  E. Nestler,et al.  Molecular Neurobiology of Drug Addiction , 1994, Neuropsychopharmacology.

[54]  S. Hyman,et al.  Addiction and the brain: The neurobiology of compulsion and its persistence , 2001, Nature Reviews Neuroscience.

[55]  B. Sproule,et al.  Characteristics of dependent and nondependent regular users of codeine. , 1999, Journal of clinical psychopharmacology.

[56]  P. Dobkin,et al.  Paternal alcoholism, paternal absence and the development of problem behaviors in boys from age six to twelve years. , 1998, Journal of studies on alcohol.

[57]  M. Le Moal,et al.  Factors that predict individual vulnerability to amphetamine self-administration. , 1989, Science.

[58]  L. Olson,et al.  NGFI-B and nor1 mRNAs are upregulated in brain reward pathways by drugs of abuse: different effects in Fischer and Lewis rats. , 2000, Brain research. Molecular brain research.

[59]  D. Surmeier,et al.  Expression of the transcription factor ΔFosB in the brain controls sensitivity to cocaine , 1999, Nature.

[60]  B. Rounsaville,et al.  Personality, substance of choice, and polysubstance involvement among substance dependent patients. , 2003, Drug and alcohol dependence.

[61]  David A. Nielsen,et al.  Genes associated with addiction , 2007, NeuroMolecular Medicine.

[62]  E. Nestler,et al.  Role for GDNF in Biochemical and Behavioral Adaptations to Drugs of Abuse , 2000, Neuron.

[63]  Richard A. Brown,et al.  Psychiatric disorders, familial factors, and cigarette smoking: II. Associations with progression to daily smoking. , 2004, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[64]  S. Shiffman,et al.  Nicotine exposure among nondependent smokers. , 1990, Archives of general psychiatry.

[65]  C. Robert Cloninger,et al.  Childhood personality predicts alcohol abuse in young adults. , 1988, Alcoholism, clinical and experimental research.

[66]  N. Rigotti,et al.  Initial symptoms of nicotine dependence in adolescents , 2000, Tobacco control.

[67]  D. Fergusson,et al.  Childhood conduct problems, attention deficit behaviors, and adolescent alcohol, tobacco, and illicit drug use , 1995, Journal of abnormal child psychology.

[68]  D. Mash,et al.  Molecular profiling of midbrain dopamine regions in cocaine overdose victims , 2003, Journal of neurochemistry.

[69]  D. W. Goodwin,et al.  Drug use by U.S. Army enlisted men in Vietnam: a follow-up on their return home. , 1974, American journal of epidemiology.

[70]  R. Jouvent,et al.  Relationships between sensation seeking and emotional symptomatology during smoking cessation with nicotine patch therapy. , 2000, Addictive behaviors.

[71]  N. Owen,et al.  Low-rate smokers. , 1995, Preventive medicine.

[72]  Ronald C. Kessler,et al.  Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. , 1994 .

[73]  M. Enoch,et al.  Pharmacogenomics of Alcohol Response and Addiction , 2003, American journal of pharmacogenomics : genomics-related research in drug development and clinical practice.

[74]  K. Kendler,et al.  Tobacco consumption in Swedish twins reared apart and reared together. , 2000, Archives of general psychiatry.

[75]  L. Robins,et al.  Narcotic use in southeast Asia and afterward. An interview study of 898 Vietnam returnees. , 1975, Archives of general psychiatry.

[76]  M. Low,et al.  Dopamine D4 Receptor-Knock-Out Mice Exhibit Reduced Exploration of Novel Stimuli , 1999, The Journal of Neuroscience.

[77]  K. Perkins,et al.  Greater sensitivity to subjective effects of nicotine in nonsmokers high in sensation seeking. , 2000, Experimental and clinical psychopharmacology.

[78]  C. L. Martin,et al.  Treated delinquent boys' substance use: onset, pattern, relationship to conduct and mood disorders. , 1995, Drug and alcohol dependence.

[79]  Y. Hurd,et al.  The Role of Dopamine, Dynorphin, and CART Systems in the Ventral Striatum and Amygdala in Cocaine Abuse , 1999, Annals of the New York Academy of Sciences.

[80]  R E Tremblay,et al.  Behavior of boys in kindergarten and the onset of substance use during adolescence. , 1997, Archives of general psychiatry.

[81]  S. Shiffman.  Tobacco “chippers” —individual differences in tobacco dependence , 2004, Psychopharmacology.

[82]  T. Arinami,et al.  Polymorphisms in genes involved in neurotransmission in relation to smoking. , 2000, European journal of pharmacology.

[83]  N. Hiroi,et al.  MAO‐B knockout mice exhibit deficient habituation of locomotor activity but normal nicotine intake , 2004, Genes, brain, and behavior.

[84]  D. Murphy,et al.  Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[85]  J. Henningfield,et al.  Pharmacodynamic effects of new de-nicotinized cigarettes. , 1999, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[86]  M. Schuckit,et al.  Conduct disorder among adolescent alcohol and drug abusers. , 1996, Journal of studies on alcohol.

[87]  George R Uhl,et al.  Substance abuse vulnerability loci: converging genome scanning data. , 2002, Trends in genetics : TIG.

[88]  S. Faraone,et al.  Genetic influences on DSM-III-R drug abuse and dependence: a study of 3,372 twin pairs. , 1996, American journal of medical genetics.

[89]  R. Gainetdinov,et al.  Experimental Genetic Approaches to Addiction , 2002, Neuron.

[90]  Richard A. Brown,et al.  Psychiatric disorders, familial factors, and cigarette smoking: III. Associations with cessation by young adulthood among daily smokers. , 2004, Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco.

[91]  S. Shiffman,et al.  Nicotine withdrawal in chippers and regular smokers: subjective and cognitive effects. , 1995, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[92]  L. Knorring,et al.  Personality disorders according to DSM-III-R and thrombocyte monoamine oxidase activity in type 1 and type 2 alcoholics. , 1996, Journal of studies on alcohol.

[93]  David Belin,et al.  Evidence for Addiction-like Behavior in the Rat , 2004, Science.

[94]  M. Bardo,et al.  Psychobiology of novelty seeking and drug seeking behavior , 1996, Behavioural Brain Research.

[95]  P. Geller,et al.  Personality disorders associated with substance use among American and Greek adolescents. , 2002, Adolescence.

[96]  D. Offord,et al.  Psychiatric disorder and substance use in adolescence. , 1991, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[97]  T. Robbins,et al.  Impulsive Choice Induced in Rats by Lesions of the Nucleus Accumbens Core , 2001, Science.

[98]  E. Nestler,et al.  Molecular basis of long-term plasticity underlying addiction , 2001, Nature Reviews Neuroscience.

[99]  P. Verbanck,et al.  Temperament and Character Inventory (TCI) personality profile and sub-typing in alcoholic patients: a controlled study. , 2001, Alcohol and alcoholism.