Abstract
Chronic exposure to cocaine is associated with neuroadaptions in stress and reward circuits that may increase susceptibility to relapse. We examined whether there are alterations in stress response and craving in abstinent cocaine-dependent individuals compared with a demographically matched group of non-addicted socially drinking community controls. Forty treatment-engaged abstinent cocaine patients (17F/23M) and 40 controls (19F/21M) were exposed to a brief 5 min guided imagery of individually calibrated stressful situations, personal drug/alcohol-related situation and a neutral-relaxing situation, one imagery per session, presented in random order. Craving, anxiety, emotion rating scales, and physiological measures were assessed. Cocaine patients reported significantly higher and more persistent stress- and cue-induced drug/alcohol craving, negative emotions, and physiological responses compared with social drinkers. In cocaine patients, stress- and cue-induced drug craving was accompanied by increased anger, fear, sadness, heart rate, and SBP. Controls reported minimal stress-induced craving and only increases in anxiety and SBP during stress exposure. Cue-induced alcohol craving was accompanied only by an increase in relaxed state. Females reported increased stress-induced anxiety and sadness compared with males, while males were emotionally and physiologically more reactive in the cue condition. These findings are the first to document functional alterations in stress- and reward-related affect and physiology in recently abstinent cocaine patients that is marked by an enhanced sensitivity to stress- and drug-related cue exposure. These data suggest that recovery from chronic cocaine abuse could be hampered by a hyper-responsive stress- and drug-craving state that increases cocaine relapse susceptibility.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Adinoff B, Junghanns K, Kiefer F, Krishnan-Sarin S (2005). Suppression of the HPA axis stress-response: implications for relapse. Alcohol Clin Exp Res 30: 585.
Ahmed SH, Koob GF (2005). Transition to drug addiction: a negative reinforcement model based on an allostatic decrease in reward function. Psychopharmacology (Berl) 180: 473–490.
Avants SK, Margolin A, Kosten TR, Cooney NL (1995). Differences between responders and nonresponders to cocaine cues in the laboratory. Addict Behav 20: 215–224.
Back SE, Brady KT, Jackson JL, Salstrom S, Zinzow H (2005). Gender differences in stress reactivity among cocaine-dependent individuals. Psychopharmacology (Berl) 180: 169–176.
Bernstein DP, Fink L (1998). Childhood Trauma Questionnaire: A Retrospective Self-Report Manual. The Psychological Corporation: San Antonio, TX.
Beveridge TJ, Smith HR, Nader MA, Porrino LJ (2005). Effects of chronic cocaine self-administration on norepinephrine transporters in the nonhuman primate brain. Psychopharmacology (Berl) 180: 781–788 [E-pub 2005 Sep 14].
Boyle GJ (1984). Reliability and validity of Izard's differential emotion scale. Pers Individ Dif 5: 747–750.
Brady KT, Back SE, Waldrop AE, McRae AL, Anton RF, Upadhyaya HP et al (2006). Cold pressor task reactivity: predictors of alcohol use among alcohol-dependent individuals with and without comorbid posttraumatic stress disorder. Alcohol Clin Exp Res 30: 938–946.
Breese GR, Chu K, Dayas CV, Funk D, Knapp DJ, Koob GF et al (2005). Stress enhancement of craving during sobriety: a risk for relapse. Alcohol Clin Exp Res 29: 185–195.
Brody L (1999). Gender, Emotion, and the Family. Harvard University Press: Cambridge, MA.
Brunova J (2004). Endocrine diseases and diabetes. Cas Lek Cesk 143: 507–511.
Callahan D, Cisin IH (1968). American drinking practices: summary of findings from a national probability sample. I. Extent of drinking by population subgroups. Q Journal Stud Alcohol 29: 130.
Casada JH, Amdur R, Larsen R, Liberzon I (1998). Psychophysiologic responsivity in posttraumatic stress disorder: generalized hyperresponsivity versus trauma specificity. Soc Biol Psyc 44: 1037–1044.
Cohen S, Kessler RC, Gordon LU (1995). Strategies for measuring stress in studies of psychiatric and physical disorders. In: Cohen S, Kessler RC, Gordon LU (eds). Measuring Stress: a Guide for Health and Social Scientists. Oxford University Press: New York. pp 3–26.
Cooney NL, Gillespie RA, Baker LH, Kaplan RF (1987). Cognitive changes after alcohol cue exposure. J Consult Clin Psychol 55: 150–155.
Eisenberg N, Fabes RA, Schaller M, Miller P, Carlo G, Poulin R et al (1991). Personality and socialization correlates of vicarious emotional responding. J Pers Soc Psychol 61: 459–470.
Erb S, Funk D, Le AD (2003). Prior, repeated exposure to cocaine potentiates locomotor responsivity to central injections of corticotropin-releasing factor (CRF) in rats. Psychopharmacology (Berl) 170: 383–389.
First MB, Spitzer RL, Gibbon M, Williams JBW (1997). Structured Clinical Interview for the DSM-IV Axis I Disorders—Patient Edition (SCID-I/P, Version 20, 4/97 Revision). New York State Psychiatric Institute: New York.
Fox HC, Berquist KL, Hong KI, Sinha R (2007). Stress-induced and alcohol cue-induced craving in recently abstinent alcohol dependent individuals. Alcoholism: Clin Exp Res 31: 395–403.
Fox HC, Garcia M, Kemp K, Milivojevic V, Kreek MJ, Sinha R (2006). Gender differences in cardiovascular and corticoadrenal response to stress and drug-cue in cocaine dependent individuals. Psychopharmacology 185: 348–357.
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 to drug-related cues. Psychoneuroendocrinology 30: 880–891.
Fuenzalida C, Emde RN, Pannabecker BJ, Stenberg C (1981). Validation of the differential emotion scale in 613 mothers. Motivation Emotion 5: 37–45.
Greeley JD, Swift W, Prescott J, Heather N (1993). Reactivity to alcohol-related cues in heavy and light drinkers. J Stud Alcohol 54: 359–368.
Haile CN, GrandPre T, Kosten TA (2001). Chronic unpredictable stress, but not chronic predictable stress, enhances the sensitivity to the behavioral effects of cocaine in rats. Psychopharmacology (Berl) 154: 213–220.
Hyman S, Fox HC, Hong K, Doebrick C, Sinha R (2007a). Stress and drug cue-induced craving in opioid dependent individuals in naltrexone treatment. Exp Clin Psychopharmacol 15: 134–143.
Hyman SM, Paliwal P, Sinha R (2007b). Childhood maltreatment, perceived stress, and stress-related coping in recently abstinent cocaine dependent adults. Psychol Addict Behav (in press).
Izard C (1972). Patterns of Emotions: A New Analysis of Anxiety and Depression. Academic Press: New York.
Kalivas PW, Stewart J (1991). Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Brain Res Rev 16: 223–244.
Kampman KM, Alterman AI, Volpicelli JR, Maany I, Muller ES, Luce DD et al (2001a). Cocaine withdrawal symptoms and initial urine toxicology results predict treatment attrition in outpatient cocaine dependence treatment. Psychol Addict Behav 15: 52–59.
Kampman KM, Dackis C, Lynch KG, Pettinati H, Tirado C, Gariti P et al (2006). A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the treatment of cocaine dependence in patients with severe cocaine withdrawal symptoms. Drug Alcohol Depend 85: 129–137.
Kampman KM, Volpicelli JR, McGinnis DE, Alterman AI, Weinrieb RM, D'Angelo L et al (1998). Reliability and validity of the Cocaine Selective Severity Assessment. Addict Behav 23: 449–461.
Kampman KM, Volpicelli JR, Mulvaney F, Alterman AI, Cornish J, Gariti P et al (2001b). Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity. Drug Alcohol Depend 63: 69–78.
Kenny PJ, Chen SA, Kitamura O, Markou A, Koob GF (2006). Conditioned withdrawal drives heroin consumption and decreases reward sensitivity. J Neurosci 26: 5894–5900.
Kenny PJ, Markou A (2005). Conditioned nicotine withdrawal profoundly decreases the activity of brain reward systems. J Neurosci 25: 6208–6212.
Kilts CD, Gross RE, Ely TD, Drexler KP (2004). The neural correlates of cue-induced craving in cocaine-dependent women. Am J Psychiatry 161: 193–194.
Koob GF, Ahmed SH, Boutrel B, Chen SA, Kenny PJ, Markou A et al (2004). Neurobiological mechanisms in the transition from drug use to drug dependence. Neurosci Biobehav Rev 27: 739–749.
Koob GF, Le Moal M (1997). Drug abuse: hedonic homeostatic dysregulation. Science 278: 52–58.
Koob GF, Le Moal M (2001). Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24: 97–129.
Laird NM, Ware JH (1982). Random-effects models for longitudinal data. Biometrics 38: 963–974.
Lepsch LB, Gonzalo LA, Magro FJ, Delucia R, Scavone C, Planeta CS (2005). Exposure to chronic stress increases the locomotor response to cocaine and the basal levels of corticosterone in adolescent rats. Addict Biol 10: 251–256.
Li CS, Kemp K, Milivojevic V, Sinha R (2005). Neuroimaging study of sex differences in the neuropathology of cocaine abuse. Gend Med 2: 174–182.
Mateo Y, Lack CM, Morgan D, Roberts DC, Jones SR (2005). Reduced dopamine terminal function and insensitivity to cocaine following cocaine binge self-administration and deprivation. Neuropsychopharmacology 30: 1455–1463.
Mendelson JH, Sholar MB, Goletiani N, Siegel AJ, Mello NK (2005). Effects of low- and high-nicotine cigarette smoking on mood states and the HPA axis in men. Neuropsychopharmacology 30: 1751–1763.
Moore RJ, Vinsant SL, Nader MA, Porrino LJ, Friedman DP (1998). Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys. Synapse 30: 88–96.
Nader MA, Daunais JB, Moore T, Nader SH, Moore RJ, Smith HR et al (2002). Effects of cocaine self-administration on striatal dopamine systems in rhesus monkeys: initial and chronic exposure. Neuropsychopharmacology 27: 35–46.
Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L et al (2005). Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine. Neuropsychopharmacology 30: 821–832.
Pariante CM (2003). Depression, stress and the adrenal axis. J Neuroendocrinol 15: 811–812.
Parsons LH, Weiss F, Koob GF (1996). Serotonin1b receptor stimulation enhances dopamine-mediated reinforcement. Psychopharmacology (Berl) 128: 150–160.
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.
Richter RM, Pich EM, Koob GF, Weiss F (1995). Sensitization of cocaine-stimulated increase in extracellular levels of corticotropin-releasing factor from the rat amygdala after repeated administration as determined by intracranial microdialysis. Neurosci Lett 187: 169–172.
Robbins SJ, Ehrman RN, Childress AR, O'Brien CP (1999). Comparing levels of cocaine cue reactivity in male and female outpatients. Drug Alcohol Depend 53: 223–230.
Sarnyai Z (1998). Neurobiology of stress and cocaine addiction. Studies on corticotropin-releasing factor in rats, monkeys, and humans. Ann NY Acad Sci 851: 371–387.
Schulteis G, Markou A, Cole M, Koob GF (1995). Decreased brain reward produced by ethanol withdrawal. Proc Natl Acad Sci USA 92: 5880–5884.
Sinha R (2001). How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158: 343–359.
Sinha R, Catapano D, O'Malley S (1999). Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacology (Berl) 142: 343–351.
Sinha R, Fuse T, Aubin LR, O'Malley SS (2000). Psychological stress, drug-related cues and cocaine craving. Psychopharmacology (Berl) 152: 140–148.
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.
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.
Sterling RC, Dean J, Weinstein SP, Murphy J, Gottheil E (2004). Gender differences in cue exposure reactivity and 9-month outcome. J Subst Abuse Treat 27: 39–44.
Volkow ND, Fowler JS, Wang GJ, Hitzemann R, Logan J, Schlyer DJ et al (1993). Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14: 169–177.
Volkow ND, Wang GJ, Fowler JS, Logan J, Hitzemannn R, Gatley SJ et al (1996). Cocaine uptake is decreased in the brain of detoxified cocaine abusers. Neuropsychopharmacology 14: 159–168.
Weiss F (2005). Neurobiology of craving, conditioned reward and relapse. Curr Opin Pharmacol 5: 9–19.
Weiss F, Markou A, Lorang MT, Koob GF (1992). Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration. Brain Res 593: 314–318.
Acknowledgements
This study was supported in part by Grants R01-DA11077 (Sinha), P50-DA16556 (Sinha), R0I-AA13892 (Sinha), K02-DA17232 (Sinha), and P50-DA16556 (Sinha) from the National Institutes of Health, Bethesda, MD, USA. We thank the staff at the Substance Abuse Treatment Unit, Clinical Neuroscience Research Unit, and the General Clinical Research Center at Yale University School of Medicine for their assistance in completing these studies.
Author information
Authors and Affiliations
Corresponding author
Additional information
DISCLOSURE/CONFLICT OF INTEREST
The authors declare that they have no competing financial interests.
Rights and permissions
About this article
Cite this article
Fox, H., Hong, KI., Siedlarz, K. et al. Enhanced Sensitivity to Stress and Drug/Alcohol Craving in Abstinent Cocaine-Dependent Individuals Compared to Social Drinkers. Neuropsychopharmacol 33, 796–805 (2008). https://doi.org/10.1038/sj.npp.1301470
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.npp.1301470
Keywords
This article is cited by
-
Beyond abstinence and relapse II: momentary relationships between stress, craving, and lapse within clusters of patients with similar patterns of drug use
Psychopharmacology (2021)
-
Bio-Behavioral Indices of Emotion Regulation: Potential Targets for Treatment in Addiction
Current Addiction Reports (2020)
-
The effect of oxytocin, gender, and ovarian hormones on stress reactivity in individuals with cocaine use disorder
Psychopharmacology (2020)
-
Ayahuasca blocks the reinstatement of methylphenidate-induced conditioned place preference in mice: behavioral and brain Fos expression evaluations
Psychopharmacology (2020)
-
Exacerbated Craving in the Presence of Stress and Drug Cues in Drug-Dependent Patients
Neuropsychopharmacology (2018)
