Current Psychiatry Reports

, 13:398 | Cite as

New Findings on Biological Factors Predicting Addiction Relapse Vulnerability

Article

Abstract

Relapse is a highly prevalent phenomenon in addiction. This paper examines the new research on identifying biological factors that contribute to addiction relapse risk. Prospective studies examining relapse risk are reviewed, and clinical, biological, and neural factors that predict relapse risk are identified. Clinical factors, patient-related factors, and subjective and behavioral measures such as depressive symptoms, stress, and drug craving all predict future relapse risk. Among biological measures, endocrine measures such as cortisol and cortisol/corticotropin (ACTH) ratio as a measure of adrenal sensitivity and serum brain-derived neurotrophic factor were also predictive of future relapse risk. Among neural measures, brain atrophy in the medial frontal regions and hyperreactivity of the anterior cingulate during withdrawal were identified as important in drug withdrawal and relapse risk. Caveats pertaining to specific drug abuse type and phase of addiction are discussed. Finally, significant implications of these findings for clinical practice are presented, with a specific focus on determining biological markers of relapse risk that may be used to identify those individuals who are most at risk of relapse in the clinic. Such markers may then be used to assess treatment response and develop specific treatments that will normalize these neural and biological sequelae so as to significantly improve relapse outcomes.

Keywords

Addiction relapse Stress dysregulation Drug craving Cortisol Cortisol/ACTH ratio Serum BDNF Anterior cingulate Biomarkers Human studies Biological factors Vulnerability 

Notes

Acknowledgment

Preparation of this review was supported by grants from the National Institutes of Health (P50-DA165556, R01-AA13892, R01-DA27230, UL1-DE019589, PL1-DA024859).

Disclosure

No potential conflict of interest relevant to this article was reported.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Brownell KD, Marlatt GA, Lichtenstein E, Wilson GT. Understanding and preventing relapse. Am Psychol. 1986;41:765–82.PubMedCrossRefGoogle Scholar
  2. 2.
    Brandon TH, Vidrine JI, Litvin EB. Relapse and relapse prevention. Annu Rev Clin Psychol. 2007;3:257–84.PubMedCrossRefGoogle Scholar
  3. 3.
    Paliwal P, Hyman SM, Sinha R. Craving predicts time to cocaine relapse: further validation of the now and brief versions of the cocaine craving questionnaire. Drug Alcohol Depend. 2008;93:252–9.PubMedCrossRefGoogle Scholar
  4. 4.
    • Hyman SM, Paliwal P, Chaplin TM, et al. Severity of childhood trauma is predictive of cocaine relapse outcomes in women but not men. Drug Alcohol Depend. 2008;92:208–16. This paper is the first to show sex differences in the association of severity of childhood trauma and cocaine relapse outcomes.PubMedCrossRefGoogle Scholar
  5. 5.
    Sinha R, Garcia M, Paliwal P, et al. Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatr. 2006;63:324–31.PubMedCrossRefGoogle Scholar
  6. 6.
    Dodge R, Sindelar J, Sinha R. The role of depressive symptoms in predicting drug abstinence in outpatient substance abuse treatment. J Subst Abus Treat. 2005;28:189–96.CrossRefGoogle Scholar
  7. 7.
    Sinha R. How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl). 2001;158:343–59.CrossRefGoogle Scholar
  8. 8.
    Shaham Y, Shalev U, Lu L, et al. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology. 2003;168:3–20.PubMedCrossRefGoogle Scholar
  9. 9.
    McKay JR, Rutherford MJ, Alterman AI, et al. An examination of the cocaine relapse process. Drug Alcohol Depend. 1995;38:35–43.PubMedCrossRefGoogle Scholar
  10. 10.
    Sinha R. Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci. 2008;1141:105–30.PubMedCrossRefGoogle Scholar
  11. 11.
    • Enoch MA. The role of early life stress as a predictor for alcohol and drug dependence. Psychopharmacology (Berl). 2011;214:17–31. This is an excellent recent review documenting high rates of early trauma in addictive disorders.CrossRefGoogle Scholar
  12. 12.
    Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science. 1997;278:52–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Koob GF, Ahmed SH, Boutrel B, et al. Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev. 2004;27:739–49.PubMedCrossRefGoogle Scholar
  14. 14.
    Volkow ND, Fowler JS. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cerebral Cortex. 2000;10:318–25.PubMedCrossRefGoogle Scholar
  15. 15.
    Kalivas PW, Volkow ND. The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatr. 2005;162:1403–13.PubMedCrossRefGoogle Scholar
  16. 16.
    Robinson TE, Berridge KC. The psychology and neurobiology of addiction: an incentive-sensitization view. Addiction. 2000;95 Suppl 2:S91–S117.PubMedGoogle Scholar
  17. 17.
    Sinha R. Modeling stress and drug craving in the laboratory: implications for addiction treatment development. Addict Biol. 2009;14:84–98.PubMedCrossRefGoogle Scholar
  18. 18.
    •• Sinha R, Fox HC, Hong KI, et al. Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes. Arch Gen Psychiatr. 2011, (epub online). This is the first study to show that provoked alcohol craving and adrenal sensitivity are predictive of subsequent alcohol relapse.Google Scholar
  19. 19.
    •• McKee S, Sinha R, Weinberger AH, et al. Stress decreases the ability to resist smoking and potentiates smoking intensity and reward. J Psychopharmacol. 2011;25(4):490–502. This is the first laboratory demonstration of stress-induced nicotine relapse.PubMedCrossRefGoogle Scholar
  20. 20.
    McRae-Clark A, Carter R, Price K, et al. Stress and cue-elicited craving and reactivity in marijuana-dependent individuals. Psychopharmacology (Berl). 2011.Google Scholar
  21. 21.
    Fox HC, Hong KI, Siedlarz K, Sinha R. Enhanced sensitivity to stress and drug/alcohol craving in abstinent cocaine-dependent individuals compared to social drinkers. Neuropsychopharmacology. 2008;33:796–805.PubMedCrossRefGoogle Scholar
  22. 22.
    Sinha R, Fox HC, Hong KA, et al. Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology. 2009;34:1198–208.PubMedCrossRefGoogle Scholar
  23. 23.
    Field M, Wiers RW, Christiansen P, et al. Acute alcohol effects on inhibitory control and implicit cognition: implications for loss of control over drinking. Alcohol Clin Exp Res. 2010;34(8):1346–52.PubMedGoogle Scholar
  24. 24.
    Constantinou N, Morgan CJ, Battistella S, et al. Attentional bias, inhibitory control and acute stress in current and former opiate addicts. Drug Alcohol Depend. 2010;109:220–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Baker TB, Piper ME, McCarthy DE, et al. Addiction motivation reformulated: an affective processing model of negative reinforcement. Psychol Rev. 2004;111:33–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Brown SA, Vik PW, McQuaid JR, et al. Severity of psychosocial stress and outcome of alcoholism treatment. J Abnorm Psychol. 1990;99:344–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Brown SA, Vik PW, Patterson TL, et al. Stress, vulnerability and adult alcohol relapse. J Stud Alcohol. 1995;56:538–45.PubMedGoogle Scholar
  28. 28.
    Greenfield SF, Kolodziej ME, Sugarman DE, et al. History of abuse and drinking outcomes following inpatient alcohol treatment: a prospective study. Drug Alcohol Depend. 2002;67:227–34.PubMedCrossRefGoogle Scholar
  29. 29.
    Epstein DH, Marrone GF, Heishman SJ, et al. Tobacco, cocaine, and heroin: craving and use during daily life. Addict Behav. 2009;35:318–24.PubMedCrossRefGoogle Scholar
  30. 30.
    •• Epstein DH, Willner-Reid J, Vahabzadeh M, et al. Real-time electronic diary reports of cue exposure and mood in the hours before cocaine and heroin craving and use. Arch Gen Psychiatr. 2009;66:88–94. This is the first study to use EMA to demonstrate the effects of real world cue and stress exposure on subsequent drug use.PubMedCrossRefGoogle Scholar
  31. 31.
    • Preston KL, Epstein DH. Stress in the daily lives of cocaine and heroin users: relationship to mood, craving, relapse triggers, and cocaine use. Psychopharmacology. 2011, (in press). This is an excellent paper illustrating of the use of recent methodologic advances with monitoring drug use daily in the real world and demonstrating how stress is associated with drug use.Google Scholar
  32. 32.
    Shiffman S. Dynamic influences on smoking relapse process. J Personal. 2005;73:1–34.CrossRefGoogle Scholar
  33. 33.
    Hall SM, Havassy BE, Wassermann DA. Commitment to abstinence and acute stress in relapse to alcohol, opiates and nicotine. J Counsel Clin Psychol. 1990;58:175–81.CrossRefGoogle Scholar
  34. 34.
    Greenfield SF, Weiss RD, Muenz LR, et al. The effect of depression on return to drinking: a prospective study. Arch Gen Psychiatr. 1998;55:259–65.PubMedCrossRefGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    Back SE, Hartwell K, DeSantis SM, et al. Reactivity to laboratory stress provocation predicts relapse to cocaine. Drug Alcohol Depend. 2010;106:21–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Coffey SF, Saladin ME, Drobes DJ, et al. Trauma and substance cue reactivity in individuals with comorbid posttraumatic stress disorder and cocaine or alcohol dependence. Drug Alcohol Depend. 2002;65:115–27.PubMedCrossRefGoogle Scholar
  38. 38.
    Sinha R, Catapano D, O’Mally S. Stress-induced craving and stress responses in cocaine dependent individuals. Psychopharmacology. 1999;142:343–51.PubMedCrossRefGoogle Scholar
  39. 39.
    Cooney NL, Litt MD, Morse PA, et al. Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol. 1997;106:243–50.PubMedCrossRefGoogle Scholar
  40. 40.
    Breese GR, Chu K, Dayas CV, et al. Stress enhancement of craving during sobriety and the risk of relapse. Alcohol Clin Exp Res. 2005;29(2):185–95.PubMedCrossRefGoogle Scholar
  41. 41.
    • Lubman DI, Yucel M, Kettle JW, et al. Responsiveness to drug cues and natural rewards in opiate addiction: associations with later heroin use. Arch Gen Psychiatr. 2009;66:205–12. This is the first study to show that reduced positive affect to drug cues and natural rewards is associated with later drug use.PubMedCrossRefGoogle Scholar
  42. 42.
    Shiffman S, Paty JA, Gnys M, et al. First lapses to smoking: within-subjects analysis of real-time reports. J Consult Clin Psychol. 1996;64:366–79.PubMedCrossRefGoogle Scholar
  43. 43.
    Kreek MJ, Koob GF. Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend. 1998;51:23–47.PubMedCrossRefGoogle Scholar
  44. 44.
    Contoreggi C, Herning RI, Na P, et al. Stress hormone responses to corticotropin-releasing hormone in substance abusers without severe comorbid psychiatric disease. Biol Psych. 2003;54:873–8.CrossRefGoogle Scholar
  45. 45.
    Al’absi M, Hatsukami DK, Davis G. Attenuated adrenocorticotropic responses to psychological stress are associated with early smoking relapse. Psychopharmacology (Berlin). 2005;181:107–17.CrossRefGoogle Scholar
  46. 46.
    Adinoff B, Junghanns K, Kiefer F, Krishnan-Sarin S. Suppression of the HPA axis stress-response: implications for relapse. Alcohol Clin Exp Res. 2005;29:1351–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Sinha R, Talih M, Malison R, et al. Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology (Berl). 2003;170:62–72.CrossRefGoogle Scholar
  48. 48.
    Fox HC, Hong KI, Siedlarz KM, et al. Sex-specific dissociations in autonomic and HPA responses to stress and cues in alcohol-dependent patients with cocaine abuse. Alcohol Alcohol. 2009;44:575–85.PubMedGoogle Scholar
  49. 49.
    Fox HC, Hong KH, Paliwal P, et al. Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine dependent females. Psychopharmacology. 2007;195:527–36.PubMedCrossRefGoogle Scholar
  50. 50.
    McDougle CJ, Black JE, Malison RT, et al. Noradrenergic dysregulation during discontinuation of cocaine use in addicts. Arch Gen Psychiatr. 1994;51:713–9.PubMedGoogle Scholar
  51. 51.
    Krystal JH, Webb E, Cooney NL, et al. Serotonergic and noradrenergic dysregulation in alcoholism: M-chrophenylpiperazine and yohimbine effects in recently detoxified alcoholics and healthy comparison subjects. Am J Psychiatr. 1996;153:83–92.PubMedGoogle Scholar
  52. 52.
    Bar KJ, Boettger MK, Neubauer R, et al. Heart rate variability and sympathetic skin response in male patients suffering from acute alcohol withdrawal syndrome. Alcohol Clin Exp Res. 2006;30:1592–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Ingjaldsson JT, Thayer JF, Laberg JC. Craving for alcohol and pre-attentive processing of alcohol stimuli. Int J Psychophysiol. 2003;49:29–39.PubMedCrossRefGoogle Scholar
  54. 54.
    Junghanns K, Backhaus J, Tietz U. Impaired serum cortisol stress response is a predictor of early relapse. Alcohol Alcohol. 2003;38:189–93.PubMedGoogle Scholar
  55. 55.
    Brady KT, Back SE, Waldrop AE, et al. Cold pressor task reactivity: predictors of alcohol use among alcohol-dependent individuals with and without comorbid posttraumatic stress disorder. Alcohol Clin Exp Res. 2006;30:938–46.PubMedCrossRefGoogle Scholar
  56. 56.
    Fatseas M, Denis C, Massida Z, et al. Cue-induced reactivity, cortisol response and substance use outcome in treated heroin dependent individuals. Biol Psychiatr. 2011, Jul 7 (Epub ahead of print).Google Scholar
  57. 57.
    Schoenbaum G, Stalnaker TA, Shaham Y. A role for BDNF in cocaine reward and relapse. Nat Neurosci. 2007;10:935–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Nestler EJ. Is there a common molecular pathway for addiction. Nat Neurosci. 2005;8:1445–9.PubMedCrossRefGoogle Scholar
  59. 59.
    •• D’Sa C, Fox HC, Hong K, et al. Increased serum brain-derived neurotrophic factor (BDNF) is predictive of cocaine relapse outcomes: a prospective study. Biological Psychiatr. 2011 (in press). This is the first study to identify a biomarker in the basal state that is significantly higher during early recovery from cocaine, and also to predict time to cocaine relapse.Google Scholar
  60. 60.
    Pfefferbaum A, Sullivan EV, Mathalon DH, et al. Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapsed alcoholics. Alcohol Clin Exp Res. 1995;19:1177–91.PubMedCrossRefGoogle Scholar
  61. 61.
    Sullivan EV, Rosenbloom MJ, Pfefferbaum A. Pattern of motor and cognitive deficits in detoxified alcoholic men. Alcohol Clin Exp Res. 2000;24:611–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Fein G, Di Sclafani V, Meyerhoff DJ. Prefrontal cortical volume reduction associated with frontal cortex function deficit in 6-week abstinent crack-cocaine dependent men. Drug Alcohol Depend. 2002;68:87–93.PubMedCrossRefGoogle Scholar
  63. 63.
    Tanabe J, Tregellas JR, Dalwani M, et al. Medial orbitofrontal cortex gray matter is reduced in abstinent substance-dependent individuals. Biol Psychiatr. 2009;65:160–4.CrossRefGoogle Scholar
  64. 64.
    Pfefferbaum A, Sullivan EV, Rosenbloom MJ, et al. A controlled study of cortical gray matter and ventricular changes in alcoholic men over a 5-year interval. Arch Gen Psychiatr. 1998;55:905–12.PubMedCrossRefGoogle Scholar
  65. 65.
    Gazdzinski S, Durazzo TC, Meyerhoff DJ. Temporal dynamics and determinants of whole brain tissue volume changes during recovery from alcohol dependence. Drug Alcohol Depend. 2005;78:263–73.PubMedCrossRefGoogle Scholar
  66. 66.
    Wrase J, Makris N, Braus DF, et al. Amygdala volume associated with alcohol abuse relapse and craving. Am J Psychiatr. 2008;165:1179–84.PubMedCrossRefGoogle Scholar
  67. 67.
    Rando K, Hong KI, Bhagwagar Z. Association of frontal and posterior cortical gray matter volume with time to alcohol relapse: a prospective study. Am J Psychiatr. 2011;168:183–92.PubMedCrossRefGoogle Scholar
  68. 68.
    Childress A, Mozely PD, McElgin W, et al. Limbic activation during cue-induced cocaine craving. Am J Psychiatr. 1999;156:11–8.PubMedGoogle Scholar
  69. 69.
    Grant S, London ED, Newlin DB, et al. Activation of memory circuits during cue-elicited cocaine craving. Proc Natl Acad Sci USA. 1996;93:12040–5.PubMedCrossRefGoogle Scholar
  70. 70.
    Kilts C, Schweitzer JB, Quinn CK, et al. Neural activity related to drug craving in cocaine addiction. Arch Gen Psychiatr. 2001;58:334–41.PubMedCrossRefGoogle Scholar
  71. 71.
    Kilts C, Gross RE, Ely TD, Drexler KP. The neural correlates of cue-induced craving in cocaine-dependent women. Am J Psychiatr. 2004;161:233–41.PubMedCrossRefGoogle Scholar
  72. 72.
    Li C-S, Kemp KA, Milivojevic V, Sinha R. Neuroimaging reveals sex differences in the neuropathology of cocaine abuse. J Gend Med. 2005;2:174–82.CrossRefGoogle Scholar
  73. 73.
    Sinha R, Li CS. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev. 2007;26:25–31.PubMedCrossRefGoogle Scholar
  74. 74.
    Sinha R, Lacadie C, Skudlarski P, et al. Neural activity associated with stress-induced cocaine craving: an fMRI study. Psychopharmacology. 2005;183(2):171–80.PubMedCrossRefGoogle Scholar
  75. 75.
    Seo D, Jia Z, Lacadie CM, et al. Sex differences in neural responses to stress and alcohol context cues. Hum Brain Mapp. 2010.Google Scholar
  76. 76.
    Volkow ND, Wang GJ, Telang F, et al. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci. 2006;26:6583–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Wong MM, Nigg JT, Zucker RA, et al. Behavioral control and resiliency in the onset of alcohol and illicit drug use: a prospective study from preschool to adolescence. Child Dev. 2006;77:1016–33.PubMedCrossRefGoogle Scholar
  78. 78.
    Grusser S, Wrase J, Klein S, et al. Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics. Psychopharmacology (Berl). 2004;175:296–302.CrossRefGoogle Scholar
  79. 79.
    Wrase J, Grusser S, Klein S, et al. Development of alcohol-associated cues and cue-induced brain activation in alcoholics. Biol Psych. 2002;17:287–91.Google Scholar
  80. 80.
    Heinz A, Siessmeier T, Wrase J, et al. Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. Am J Psychiatr. 2004;161:1783–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Martinez D, Gil R, Slifstein M, et al. Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatr. 2005;58:779–86.CrossRefGoogle Scholar
  82. 82.
    Martinez D, Kim JH, Krystal J, Abi-Dargham A. Imaging the neurochemistry of alcohol and substance abuse. Neuroimaging Clin N Am. 2007;17:539–55.PubMedCrossRefGoogle Scholar
  83. 83.
    Ersche KD, Clark L, London M, et al. Profile of executive and memory function associated with amphetamine and opiate dependence. Neuropsychopharmacology. 2006;31:1036–47.PubMedCrossRefGoogle Scholar
  84. 84.
    Ersche KD, Fletcher PC, Lewis SJ, et al. Abnormal frontal activations related to decision-making in current and former amphetamine and opiate dependent individuals. Psychopharmacology (Berl). 2005;180:612–23.CrossRefGoogle Scholar
  85. 85.
    Ersche KD, Roiser JP, Robbins TW, Sahakian BJ. Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans. Psychopharmacology (Berl). 2008;197:421–31.CrossRefGoogle Scholar
  86. 86.
    Hester R, Garavan H. Executive dysfunction in cocaine addiction: evidence for discordant frontal, cingulate, and cerebellar activity. J Neurosci. 2004;24:11017–22.PubMedCrossRefGoogle Scholar
  87. 87.
    Kaufman J, Ross TJ, Stein EA, Garavan H. Cingulate hypoactivity in cocaine users during a GO-NOGO task as revealed by event-related functional magnetic resonance imaging. J Neurosci. 2003;23:7839–43.PubMedGoogle Scholar
  88. 88.
    Li CS, Sinha R. Inhibitory control and emotional stress regulation: neuroimaging evidence for frontal-limbic dysfunction in psycho-stimulant addiction. Neurosci Biobehav Rev. 2008;32:581–97.PubMedCrossRefGoogle Scholar
  89. 89.
    Noel X, Bechara A, Dan B, et al. Response inhibition deficit is involved in poor decision making under risk in nonamnesic individuals with alcoholism. Neuropsychology. 2007;21:778–86.PubMedCrossRefGoogle Scholar
  90. 90.
    Paulus MP, Tapert SF, Schuckit MA. Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse. Arch Gen Psychiatr. 2005;62:761–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Kosten TR, Scanley BE, Tucker KA, et al. Cue-induced brain activity changes and relapse in cocaine dependent patients. Neuropsychopharm. 2006;31:644–50.CrossRefGoogle Scholar
  92. 92.
    • Azizian A, Nestor LJ, Payer D, et al. Smoking reduces conflict-related anterior cingulate activity in abstinent cigarette smokers performing a Stroop task. Neuropsychopharmacology. 2010;35:775–82. This paper identified the specific effect of nicotine withdrawal and smoking on anterior cingulate function.PubMedCrossRefGoogle Scholar
  93. 93.
    Naqvi NH, Rudrauf D, Damasio H, Bechara A. Damage to the insula disrupts addiction to cigarette smoking. Science. 2007;315(5811):531–4.PubMedCrossRefGoogle Scholar
  94. 94.
    Sinha R, Shaham Y, Heilig M. Translational and reverse translational research on the role of stress in drug craving and relapse. Psychopharmacology (Berl). 2011.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Yale Interdisciplinary Stress Center; Department of PsychiatryYale University School of MedicineNew HavenUSA

Personalised recommendations