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Laboratory and Real-World Experimental Approaches to Understanding Alcohol Relapse

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Current Topics in Behavioral Neurosciences

Abstract

Alcohol use disorder is highly prevalent and high risk of relapse remains a significant treatment challenge. Therefore, the utility of human laboratory models of relapse to further the understanding of psychobiological mechanisms that precipitate relapse risk and allow testing of novel interventions could be of benefit in expediting the development of effective treatments to target high relapse risk. Stress is a risk factor for the development of AUD and for relapse, and furthermore, chronic alcohol use leads to adaptations in central and peripheral stress biology. Here, we review our efforts to assess the integrity of these stress pathways in individuals with alcohol use disorder and whether adaptations in these systems play a role in relapse risk. Using validated human laboratory procedures to model two of the most common situations that contribute to relapse risk, namely stress and alcohol cues, we review how such models in the laboratory can predict subsequent relapse, and how we can measure specific identified biobehavioral markers of relapse effectively and ecologically in the real world. Finally, we discuss the significant implications of these findings for the development of novel and effective interventions that target stress dysregulation and craving as risk factors to treatment.

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References

  • Adinoff B, Risherflowers D, Dejong J, Ravitz B, Bone GHA, Nutt DJ, Roehrich L, Martin PR, Linnoila M (1991) Disturbances of hypothalamic-pituitary-adrenal axis functioning during ethanol withdrawal in 6 men. Am J Psychiatry 148:1023–1025

    Google Scholar 

  • Adinoff B, Iranmanesh A, Veldhuis J, Fisher L (1998) Disturbances of the stress response: the role of the HPA axis during alcohol withdrawal and abstinence. Alcohol Health Res World 22:67–72

    Google Scholar 

  • Adinoff B, Ruether K, Krebaum S, Iranmanesh A, Williams MJ (2003) Increased salivary cortisol concentrations during chronic alcohol intoxication in a naturalistic clinical sample of men. Alcohol Clin Exp Res 27:1420–1427

    Google Scholar 

  • Adinoff B, Junghanns K, Kiefer F, Krishnan-Sarin S (2005) Suppression of the HPA axis stress-response: implications for relapse. Alcohol Clin Exp Res 29:1351–1355

    Google Scholar 

  • al’Absi M, Bongard S, Lovallo WR (2000) Adrenocorticotropin responses to interpersonal stress: effects of overt anger expression style and defensiveness. Int J Psychophysiol 37:257–265

    Google Scholar 

  • al’Absi M, Hatsukami D, Davis GL (2005) Attenuated adrenocorticotropic responses to psychological stress are associated with early smoking relapse. Psychopharmacology (Berl) 181:107–117

    Google Scholar 

  • Almeida DM, Wethington E, Kessler RC (2002) The daily inventory of stressful events: an interview-based approach for measuring daily stressors. Assessment 9:41–55

    Google Scholar 

  • Ansell EB, Rando K, Tuit K, Guarnaccia J, Sinha R (2012) Cumulative adversity and smaller gray matter volume in medial prefrontal, anterior cingulate, and insula regions. Biol Psychiatry 72:57–64

    Google Scholar 

  • Armeli S, Tennen H, Affleck G, Kranzler HR (2000) Does affect mediate the association between daily events and alcohol use? J Stud Alcohol 61:862–871

    Google Scholar 

  • Arnsten A, Mazure CM, Sinha R (2012) This is your brain in meltdown. Sci Am 306:48–53

    Google Scholar 

  • Ashare RL, Sinha R, Lampert R, Weinberger AH, Anderson GM, Lavery ME, Yanagisawa K, McKee SA (2012) Blunted vagal reactivity predicts stress-precipitated tobacco smoking. Psychopharmacology (Berl) 220:259–268

    Google Scholar 

  • Blaine SK, Sinha R (2017) Alcohol, stress, and glucocorticoids: from risk to dependence and relapse in alcohol use disorders. Neuropharmacology 122:136–147

    Google Scholar 

  • Blaine SK, Nautiyal N, Hart R, Guarnaccia JB, Sinha R (2019) Craving, cortisol and behavioral alcohol motivation responses to stress and alcohol cue contexts and discrete cues in binge and non-binge drinkers. Addict Biol 24:1096–1108

    Google Scholar 

  • Blaine SK, Wemm S, Fogelman N, Lacadie C, Seo D, Scheinost D, Sinha R (2020) Association of prefrontal-striatal functional pathology with alcohol abstinence days at treatment initiation and heavy drinking after treatment initiation. Am J Psychiatry 177:1048–1059

    Google Scholar 

  • Brady KT, Sinha R (2005) Co-occurring mental and substance use disorders: the neurobiological effects of chronic stress. Am J Psychiatry 162:1483–1493

    Google Scholar 

  • Brandon TH, Vidrine JI, Litvin EB (2007) Relapse and relapse prevention. Annu Rev Clin Psychol 3:257–284

    Google Scholar 

  • Carliner H, Gary D, McLaughlin KA, Keyes KM (2017) Trauma exposure and externalizing disorders in adolescents: results from the National Comorbidity Survey Adolescent Supplement. J Am Acad Child Adolesc Psychiatry 56:755–764 e3

    Google Scholar 

  • Chaplin TM, Hong K, Bergquist K, Sinha R (2008) Gender differences in response to emotional stress: an assessment across subjective, behavioral, and physiological domains and relations to alcohol craving. Alcohol Clin Exp Res 32:1242–1250

    Google Scholar 

  • Chaplin TM, Sinha R, Simmons JA, Healy SM, Mayes LC, Hommer RE, Crowley MJ (2012) Parent-adolescent conflict interactions and adolescent alcohol use. Addict Behav 37:605–612

    Google Scholar 

  • Chaplin TM, Visconti KJ, Molfese PJ, Susman EJ, Klein LC, Sinha R, Mayes LC (2015) Prenatal cocaine exposure differentially affects stress responses in girls and boys: associations with future substance use. Dev Psychopathol 27:163–180

    Google Scholar 

  • Cleck JN, Blendy JA (2008) Making a bad thing worse: adverse effects of stress on drug addiction. J Clin Invest 118:454–461

    Google Scholar 

  • Cook EW 3rd, Melamed BG, Cuthbert BN, McNeil DW, Lang PJ (1988) Emotional imagery and the differential diagnosis of anxiety. J Consult Clin Psychol 56:734–740

    Google Scholar 

  • Costa A, Bono G, Martignoni E, Merlo P, Sances G, Nappi G (1996) An assessment of hypothalamo-pituitary-adrenal axis functioning in non-depressed, early abstinent alcoholics. Psychoneuroendocrinology 21:263–275

    Google Scholar 

  • Dai X, Thavundayil J, Gianoulakis C (2002) Response of the hypothalamic-pituitary-adrenal axis to stress in the absence and presence of ethanol in subjects at high and low risk of alcoholism. Neuropsychopharmacology 27:442–452

    Google Scholar 

  • Dennis PA, Watkins LL, Calhoun PS, Oddone A, Sherwood A, Dennis MF, Rissling MB, Beckham JC (2014) Posttraumatic stress, heart rate variability, and the mediating role of behavioral health risks. Psychosom Med 76:629–637

    Google Scholar 

  • Drobes DJ, Tiffany ST (1997) Induction of smoking urge through imaginal and in vivo procedures: physiological and self-report manifestations. J Abnorm Psychol 106:15–25

    Google Scholar 

  • D'Sa C, Dileone RJ, Anderson GM, Sinha R (2012) Serum and plasma brain-derived neurotrophic factor (BDNF) in abstinent alcoholics and social drinkers. Alcohol 46:253–259

    Google Scholar 

  • Ehrenreich H, Schuck J, Stender N, Pilz J, Gefeller O, Schilling L, Poser W, Kaw S (1997) Endocrine and hemodynamic effects of stress versus systemic CRF in alcoholics during early and medium term abstinence. Alcohol Clin Exp Res 21:1285–1293

    Google Scholar 

  • Errico AL, Parsons OA, King AC, Lovallo WR (1993) Attenuated cortisol response to biobehavioral stressors in sober alcoholics. J Stud Alcohol 54:393–398

    Google Scholar 

  • Evans BE, Greaves-Lord K, Euser AS, Franken IH, Huizink AC (2012) The relation between hypothalamic-pituitary-adrenal (HPA) axis activity and age of onset of alcohol use. Addiction 107:312–322

    Google Scholar 

  • Evans BE, Greaves-Lord K, Euser AS, Koning T, Tulen JH, Franken IH, Huizink AC (2015) Blunted heart rate response as a potential endophenotype of substance use disorders: evidence from high-risk youth. Front Pediatr 3:66

    Google Scholar 

  • Foa EB, Kozak MJ (1986) Emotional processing of fear: exposure to corrective information. Psychol Bull 99:20–35

    Google Scholar 

  • Fox HC, Talih M, Malison R, Anderson GM, Kreek MJ, Sinha R (2005) Frequency of recent cocaine and alcohol use affects drug craving and associated responses to stress and drug-related cues. Psychoneuroendocrinology 30:880–891

    Google Scholar 

  • Fox HC, Garcia M Jr, Kemp K, Milivojevic V, Kreek MJ, Sinha R (2006) Gender differences in cardiovascular and corticoadrenal response to stress and drug cues in cocaine dependent individuals. Psychopharmacology (Berl) 185:348–357

    Google Scholar 

  • Fox HC, Bergquist KL, Hong KI, Sinha R (2007) Stress-induced and alcohol cue-induced craving in recently abstinent alcohol-dependent individuals. Alcohol Clin Exp Res 31:395–403

    Google Scholar 

  • Fox HC, Hong KI, Siedlarz K, Sinha R (2008) Enhanced sensitivity to stress and drug/alcohol craving in abstinent cocaine-dependent individuals compared to social drinkers. Neuropsychopharmacology 33:796–805

    Google Scholar 

  • Fox HC, Hong KI, Siedlarz KM, Bergquist K, Anderson G, Kreek MJ, Sinha R (2009) Sex-specific dissociations in autonomic and HPA responses to stress and cues in alcohol-dependent patients with cocaine abuse. Alcohol Alcohol 44:575–585

    Google Scholar 

  • Fox HC, Seo D, Tuit K, Hansen J, Kimmerling A, Morgan PT, Sinha R (2012) Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings. J Psychopharmacol 26:958–972

    Google Scholar 

  • Fox HC, Sofuoglu M, Morgan PT, Tuit KL, Sinha R (2013) The effects of exogenous progesterone on drug craving and stress arousal in cocaine dependence: impact of gender and cue type. Psychoneuroendocrinology 38:1532–1544

    Google Scholar 

  • Heilig M, Thorsell A, Sommer WH, Hansson AC, Ramchandani VA, George DT, Hommer D, Barr CS (2010) Translating the neuroscience of alcoholism into clinical treatments: from blocking the buzz to curing the blues. Neurosci Biobehav Rev 35:334–344

    Google Scholar 

  • Hinnant JB, Erath SA, El-Sheikh M (2015) Harsh parenting, parasympathetic activity, and development of delinquency and substance use. J Abnorm Psychol 124:137–151

    Google Scholar 

  • Hyman SM, Paliwal P, Chaplin TM, Mazure CM, Rounsaville BJ, Sinha R (2008) Severity of childhood trauma is predictive of cocaine relapse outcomes in women but not men. Drug Alcohol Depend 92:208–216

    Google Scholar 

  • Inder WJ, Joyce PR, Wells JE, Evans MJ, Ellis MJ, Mattioli L, Donald RA (1995) The acute effects of oral ethanol on the hypothalamic-pituitary-adrenal axis in normal human subjects. Clin Endocrinol (Oxf) 42:65–71

    Google Scholar 

  • Ingjaldsson JT, Laberg JC, Thayer JF (2003) Reduced heart rate variability in chronic alcohol abuse: relationship with negative mood, chronic thought suppression, and compulsive drinking. Biol Psychiatry 54:1427–1436

    Google Scholar 

  • Junghanns K, Backhaus J, Tietz U, Lange W, Bernzen J, Wetterling T, Rink L, Driessen M (2003) Impaired serum cortisol stress response is a predictor of early relapse. Alcohol Alcohol 38:189–193

    Google Scholar 

  • King AC, McNamara PJ, Hasin DS, Cao D (2014) Alcohol challenge responses predict future alcohol use disorder symptoms: a 6-year prospective study. Biol Psychiatry 75:798–806

    Google Scholar 

  • King AC, Hasin D, O'Connor SJ, McNamara PJ, Cao D (2016) A prospective 5-year re-examination of alcohol response in heavy drinkers progressing in alcohol use disorder. Biol Psychiatry 79:489–498

    Google Scholar 

  • Koob GF (2009) Dynamics of neuronal circuits in addiction: reward, antireward, and emotional memory. Pharmacopsychiatry 42(Suppl 1):S32–S41

    Google Scholar 

  • Koob G, Kreek MJ (2007) Stress, dysregulation of drug reward pathways, and the transition to drug dependence. Am J Psychiatry 164:1149–1159

    Google Scholar 

  • Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A, O'Dell LE, Parsons LH, Sanna PP (2004) Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27:739–749

    Google Scholar 

  • Kreek MJ, Koob GF (1998) Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51:23–47

    Google Scholar 

  • Kutscher S, Heise DJ, Banger M, Saller B, Michel MC, Gastpar M, Schedlowski M, Exton M (2002) Concomitant endocrine and immune alterations during alcohol intoxication and acute withdrawal in alcohol-dependent subjects. Neuropsychobiology 45:144–149

    Google Scholar 

  • Kwako LE, Spagnolo PA, Schwandt ML, Thorsell A, George DT, Momenan R, Rio DE, Huestis M, Anizan S, Concheiro M, Sinha R, Heilig M (2015) The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study. Neuropsychopharmacology 40:1053–1063

    Google Scholar 

  • Laucht M, Treutlein J, Schmid B, Blomeyer D, Becker K, Buchmann AF, Schmidt MH, Esser G, Jennen-Steinmetz C, Rietschel M, Zimmermann US, Banaschewski T (2009) Impact of psychosocial adversity on alcohol intake in young adults: moderation by the LL genotype of the serotonin transporter polymorphism. Biol Psychiatry 66:102–109

    Google Scholar 

  • Lee S, Rivier C (1997) An initial, three-day-long treatment with alcohol induces a long-lasting phenomenon of selective tolerance in the activity of the rat hypothalamic-pituitary-adrenal axis. J Neurosci 17:8856–8866

    Google Scholar 

  • Li CS, Sinha R (2008) Inhibitory control and emotional stress regulation: neuroimaging evidence for frontal-limbic dysfunction in psycho-stimulant addiction. Neurosci Biobehav Rev 32:581–597

    Google Scholar 

  • Lovallo WR, Dickensheets SL, Myers DA, Thomas TL, Nixon SJ (2000) Blunted stress cortisol response in abstinent alcoholic and polysubstance-abusing men. Alcohol Clin Exp Res 24:651–658

    Google Scholar 

  • Martins JS, Fogelman N, Wemm S, Hwang S, Sinha R (2022) Alcohol craving and withdrawal at treatment entry prospectively predict alcohol use outcomes during outpatient treatment. Drug Alcohol Depend 231:109253

    Google Scholar 

  • Mayberg HS, Liotti M, Brannan SK, McGinnis S, Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC, Lancaster JL, Fox PT (1999) Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 156:675–682

    Google Scholar 

  • McKay JR, Rutherford MJ, Alterman AI, Cacciola JS, Kaplan MR (1995) An examination of the cocaine relapse process. Drug Alcohol Depend 38:35–43

    Google Scholar 

  • McKay JR, Rutherford MJ, Cacciola JS, Kabasakalian-McKay R, Alterman AI (1996) Gender differences in the relapse experiences of cocaine patients. J Nerv Ment Dis 184:616–622

    Google Scholar 

  • McKee SA, Sinha R, Weinberger AH, Sofuoglu M, Harrison EL, Lavery M, Wanzer J (2011) Stress decreases the ability to resist smoking and potentiates smoking intensity and reward. J Psychopharmacol 25:490–502

    Google Scholar 

  • McNeil DW, Vrana SR, Melamed BG, Cuthbert BN, Lang PJ (1993) Emotional imagery in simple and social phobia: fear versus anxiety. J Abnorm Psychol 102:212–225

    Google Scholar 

  • Meaney MJ, Brake W, Gratton A (2002) Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse? Psychoneuroendocrinology 27:127–138

    Google Scholar 

  • Mello NK (2010) Hormones, nicotine, and cocaine: clinical studies. Horm Behav 58:57–71

    Google Scholar 

  • Milivojevic V, Sinha R (2017) Targeting stress pathophysiology to improve alcoholism relapse outcomes. Neuropsychopharmacology 42:987–988

    Google Scholar 

  • Milivojevic V, Sinha R (2018) Central and peripheral biomarkers of stress response for addiction risk and relapse vulnerability. Trends Mol Med 24:173–186

    Google Scholar 

  • Milivojevic V, Fox HC, Sofuoglu M, Covault J, Sinha R (2016) Effects of progesterone stimulated allopregnanolone on craving and stress response in cocaine dependent men and women. Psychoneuroendocrinology 65:44–53

    Google Scholar 

  • Milivojevic V, Fox HC, Jayaram-Lindstrom N, Hermes G, Sinha R (2017) Sex differences in guanfacine effects on stress-induced stroop performance in cocaine dependence. Drug Alcohol Depend 179:275–279

    Google Scholar 

  • Milivojevic V, Angarita GA, Hermes G, Sinha R, Fox HC (2020) Effects of prazosin on provoked alcohol craving and autonomic and neuroendocrine response to stress in alcohol use disorder. Alcohol Clin Exp Res 44:1488–1496

    Google Scholar 

  • Milivojevic V, Sullivan L, Tiber J, Charron L, Fogelman N, Hermes G, Sinha R (2022a) The neuroactive steroid precursor pregnenolone reduces stress- and cue- provoked alcohol craving, and normalizes autonomic arousal responses in individuals with AUD. Alcohol Clin Exp Res 46:70–289. https://doi.org/10.1111/acer.14833

    Article  Google Scholar 

  • Milivojevic V, Charron L, Sullivan L, Fogelman N, Hermes G, Sinha R (2022b) The neuroactive steroid precursor pregnenolone normalizes HPA axis response to stress in individuals with alcohol use disorder. Alcoholims 46:70–289. https://doi.org/10.1111/acer.14833

    Article  Google Scholar 

  • Moss HB, Vanyukov MM, Martin CS (1995) Salivary cortisol responses and the risk for substance abuse in prepubertal boys. Biol Psychiatry 38:547–555

    Google Scholar 

  • Moss HB, Vanyukov M, Yao JK, Kirillova GP (1999) Salivary cortisol responses in prepubertal boys: the effects of parental substance abuse and association with drug use behavior during adolescence. Biol Psychiatry 45:1293–1299

    Google Scholar 

  • Nelson RA, Boyd SJ, Ziegelstein RC, Herning R, Cadet JL, Henningfield JE, Schuster CR, Contoreggi C, Gorelick DA (2006) Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans. Drug Alcohol Depend 82:19–24

    Google Scholar 

  • O'Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek MJ (2002) Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo-pituitary-adrenocortical axis. Psychopharmacology (Berl) 160:19–29

    Google Scholar 

  • Orr SP, Pitman RK, Lasko NB, Herz LR (1993) Psychophysiological assessment of posttraumatic stress disorder imagery in World War II and Korean combat veterans. J Abnorm Psychol 102:152–159

    Google Scholar 

  • Paliwal P, Hyman SM, Sinha R (2008) Craving predicts time to cocaine relapse: further validation of the now and brief versions of the cocaine craving questionnaire. Drug Alcohol Depend 93:252–259

    Google Scholar 

  • Pitman RK, Orr SP, Forgue DF, de Jong JB, Claiborn JM (1987) Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch Gen Psychiatry 44:970–975

    Google Scholar 

  • Pomerleau OF, Pomerleau CS (1990) Cortisol response to a psychological stressor and/or nicotine. Pharmacol Biochem Behav 36:211–213

    Google Scholar 

  • Preston KL, Schroeder JR, Kowalczyk WJ, Phillips KA, Jobes ML, Dwyer M, Vahabzadeh M, Lin JL, Mezghanni M, Epstein DH (2018) End-of-day reports of daily hassles and stress in men and women with opioid-use disorder: relationship to momentary reports of opioid and cocaine use and stress. Drug Alcohol Depend 193:21–28

    Google Scholar 

  • Rando K, Chaplin TM, Potenza MN, Mayes L, Sinha R (2013) Prenatal cocaine exposure and gray matter volume in adolescent boys and girls: relationship to substance use initiation. Biol Psychiatry 74:482–489

    Google Scholar 

  • Rao U (2010) Comorbidity between depressive and addictive disorders in adolescents: role of stress and Hpa activity. US Psyc 3:39–43

    Google Scholar 

  • Rao U, Morris MC (2015) Cortisol responses to psychosocial stress: the role of childhood maltreatment and depression. Int J Public Ment Health Neurosci 2

    Google Scholar 

  • Rao U, Hammen CL, London ED, Poland RE (2009) Contribution of hypothalamic-pituitary-adrenal activity and environmental stress to vulnerability for smoking in adolescents. Neuropsychopharmacology 34:2721–2732

    Google Scholar 

  • Rasmussen DD, Wilkinson CW, Raskind MA (2006) Chronic daily ethanol and withdrawal: 6. Effects on rat sympathoadrenal activity during “abstinence”. Alcohol 38:173–177

    Google Scholar 

  • Rechlin T, Orbes I, Weis M, Kaschka WP (1996) Autonomic cardiac abnormalities in alcohol-dependent patients admitted to a psychiatric department. Clin Auton Res 6:119–122

    Google Scholar 

  • Richardson HN, Lee SY, O'Dell LE, Koob GF, Rivier CL (2008) Alcohol self-administration acutely stimulates the hypothalamic-pituitary-adrenal axis, but alcohol dependence leads to a dampened neuroendocrine state. Eur J Neurosci 28:1641–1653

    Google Scholar 

  • Schwabe L, Dickinson A, Wolf OT (2011) Stress, habits, and drug addiction: a psychoneuroendocrinological perspective. Exp Clin Psychopharmacol 19:53–63

    Google Scholar 

  • Schwandt ML, Cortes CR, Kwako LE, George DT, Momenan R, Sinha R, Grigoriadis DE, Pich EM, Leggio L, Heilig M (2016) The CRF1 antagonist verucerfont in anxious alcohol-dependent women: translation of neuroendocrine, but not of anti-craving effects. Neuropsychopharmacology 41:2818–2829

    Google Scholar 

  • Seo D, Lacadie CM, Tuit K, Hong KI, Constable RT, Sinha R (2013) Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk. JAMA Psychiatry 70:727–739

    Google Scholar 

  • Seyler LE Jr, Fertig J, Pomerleau O, Hunt D, Parker K (1984) The effects of smoking on ACTH and cortisol secretion. Life Sci 34:57–65

    Google Scholar 

  • Shalev AY, Orr SP, Pitman RK (1993) Psychophysiologic assessment of traumatic imagery in Israeli civilian patients with posttraumatic stress disorder. Am J Psychiatry 150:620–624

    Google Scholar 

  • Shively CA, Mietus JE, Grant KA, Goldberger AL, Bennett AJ, Willard SL (2007) Effects of chronic moderate alcohol consumption and novel environment on heart rate variability in primates (Macaca fascicularis). Psychopharmacology (Berl) 192:183–191

    Google Scholar 

  • Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158:343–359

    Google Scholar 

  • Sinha R (2007) The role of stress in addiction relapse. Curr Psychiatry Rep 9:388–395

    Google Scholar 

  • Sinha R (2008) Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141:105–130

    Google Scholar 

  • Sinha R (2009) Modeling stress and drug craving in the laboratory: implications for addiction treatment development. Addict Biol 14:84–98

    Google Scholar 

  • Sinha R (2012) How does stress lead to risk of alcohol relapse? Alcohol Res 34:432–440

    Google Scholar 

  • Sinha R (2013a) The clinical neurobiology of drug craving. Curr Opin Neurobiol 23:649–654

    Google Scholar 

  • Sinha R (2013b) Modeling relapse situations in the human laboratory. Curr Top Behav Neurosci 13:379–402

    Google Scholar 

  • Sinha R, Tuit K (2012) Imagery script development procedures manual. CreateSpace Independent Publishing

    Google Scholar 

  • Sinha R, Fuse T, Aubin LR, O'Malley SS (2000) Psychological stress, drug-related cues and cocaine craving. Psychopharmacology (Berl) 152:140–148

    Google Scholar 

  • Sinha R, Talih M, Malison R, Cooney N, Anderson GM, Kreek MJ (2003) Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states. Psychopharmacology (Berl) 170:62–72

    Google Scholar 

  • Sinha R, Garcia M, Paliwal P, Kreek MJ, Rounsaville BJ (2006) Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry 63:324–331

    Google Scholar 

  • Sinha R, Fox HC, Hong KA, Bergquist K, Bhagwagar Z, Siedlarz KM (2009) Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology 34:1198–1208

    Google Scholar 

  • Sinha R, Fox HC, Hong KA, Hansen J, Tuit K, Kreek MJ (2011) Effects of Adrenal Sensitivity, Stress- and Cue-Induced Craving, and Anxiety on Subsequent Alcohol Relapse and Treatment Outcomes. Arch Gen Psychiatry 68(9):942–952

    Google Scholar 

  • Sinha R, Lacadie CM, Constable RT, Seo D (2016) Dynamic neural activity during stress signals resilient coping. Proc Natl Acad Sci U S A 113:8837–8842

    Google Scholar 

  • Sinha R, Wemm S, Fogelman N, Milivojevic V, Morgan PM, Angarita GA, Hermes G, Fox HC (2021) Moderation of Prazosin’s efficacy by alcohol withdrawal symptoms. Am J Psychiatry 178:447–458

    Google Scholar 

  • Sinha R, Fogelman N, Wemm S, Angarita G, Seo D, Hermes G (2022) Alcohol withdrawal symptoms predict corticostriatal dysfunction that is reversed by prazosin treatment in alcohol use disorder. Addict Biol 27:e13116

    Google Scholar 

  • Stewart J, de Wit H, Eikelboom R (1984) Role of unconditioned and conditioned drug effects in the self-administration of opiates and stimulants. Psychol Rev 91:251–268

    Google Scholar 

  • Thayer JF, Hall M, Sollers JJ 3rd, Fischer JE (2006) Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: evidence for impaired inhibitory control of the HPA axis in heavy drinkers. Int J Psychophysiol 59:244–250

    Google Scholar 

  • Tiffany ST, Drobes DJ (1991) The development and initial validation of a questionnaire on smoking urges. Br J Addict 86:1467–1476

    Google Scholar 

  • Tiffany ST, Hakenewerth DM (1991) The production of smoking urges through an imagery manipulation: psychophysiological and verbal manifestations. Addict Behav 16:389–400

    Google Scholar 

  • Tiffany ST, Wray JM (2012) The clinical significance of drug craving. Ann N Y Acad Sci 1248:1–17

    Google Scholar 

  • Tyrka AR, Ridout KK, Parade SH (2016) Childhood adversity and epigenetic regulation of glucocorticoid signaling genes: associations in children and adults. Dev Psychopathol 28:1319–1331

    Google Scholar 

  • US Department of Health and Human Services (HHS), Office of the Surgeon General (2016) Facing addiction in America: the surgeon general’s report on alcohol, drugs, and health, HHS

    Google Scholar 

  • Vafaie N, Kober H (2022) Association of drug cues and craving with drug use and relapse: a systematic review and meta-analysis. JAMA Psychiatry 79:641–650

    Google Scholar 

  • Van Dam NT, Rando K, Potenza MN, Tuit K, Sinha R (2014) Childhood maltreatment, altered limbic neurobiology, and substance use relapse severity via trauma-specific reductions in limbic gray matter volume. JAMA Psychiatry 71:917–925

    Google Scholar 

  • Vendruscolo LF, Estey D, Goodell V, Macshane LG, Logrip ML, Schlosburg JE, McGinn MA, Zamora-Martinez ER, Belanoff JK, Hunt HJ, Sanna PP, George O, Koob GF, Edwards S, Mason BJ (2015) Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. J Clin Invest 125:3193–3197

    Google Scholar 

  • Wand GS, Dobs AS (1991) Alterations in the hypothalamic-pituitary-adrenal axis in actively drinking alcoholics. J Clin Endocrinol Metab 72:1290–1295

    Google Scholar 

  • Wemm SE, Sinha R (2019) Drug-induced stress responses and addiction risk and relapse. Neurobiol Stress 10:100148

    Google Scholar 

  • Wemm SE, Larkin C, Hermes G, Tennen H, Sinha R (2019) A day-by-day prospective analysis of stress, craving and risk of next day alcohol intake during alcohol use disorder treatment. Drug Alcohol Depend 204:107569

    Google Scholar 

  • Wemm SE, Tennen H, Sinha R, Seo D (2022) Daily stress predicts later drinking initiation via craving in heavier social drinkers: a prospective in-field daily diary study. J Psychopathol Clin Sci 131:780–792

    Google Scholar 

  • Xu K, Hong KA, Zhou Z, Hauger RL, Goldman D, Sinha R (2012) Genetic modulation of plasma NPY stress response is suppressed in substance abuse: association with clinical outcomes. Psychoneuroendocrinology 37:554–564

    Google Scholar 

  • Yuksel R, Yuksel RN, Sengezer T, Dane S (2016) Autonomic cardiac activity in patients with smoking and alcohol addiction by heart rate variability analysis. Clin Invest Med 39:27519

    Google Scholar 

  • Zhou Y, Franck J, Spangler R, Maggos CE, Ho A, Kreek MJ (2000) Reduced hypothalamic POMC and anterior pituitary CRF1 receptor mRNA levels after acute, but not chronic, daily “binge” intragastric alcohol administration. Alcohol Clin Exp Res 24:1575–1582

    Google Scholar 

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Acknowledgments

Preparation of this review was supported by grants R01-AA026514, R01-AA013892, R01-AA029113 (Sinha) from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and K01-DA046561 (Milivojevic) from the National Institute on Drug Abuse (NIDA) from the National Institutes of Health (NIH). The authors declare no conflict of interest.

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Correspondence to Rajita Sinha .

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Milivojevic, V., Sinha, R. (2023). Laboratory and Real-World Experimental Approaches to Understanding Alcohol Relapse. In: Current Topics in Behavioral Neurosciences. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7854_2023_456

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  • DOI: https://doi.org/10.1007/7854_2023_456

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