Skip to main content
Log in

Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Environmental stimuli associated with cocaine are known to elicit drug craving and increase the likelihood of relapse. However, the psychobiological changes that occur with exposure to these stimuli and in episodes of drug craving are not well understood. This study examined the response of brain stress circuits to environmental stimuli that are known to increase cocaine craving in cocaine dependent individuals.

Methods

Fifty-four treatment seeking cocaine dependent individuals, who were admitted to an inpatient treatment research unit for 2–4 weeks, participated in three laboratory sessions. Subjects were exposed to a brief 5-min guided imagery procedure that involved imagining a recent personal stressful situation, a drug-related situation and a neutral-relaxing situation, one imagery per session presented in random order. Subjective ratings of craving and anxiety, cardiovascular measures, and plasma levels of adrenocorticotrophic hormone (ACTH), cortisol, prolactin, norepinephrine (NE) and epinephrine (EPI) were assessed.

Results

Exposure to stress and to drug cues each resulted in significant increases in cocaine craving and subjective anxiety, pulse rate, systolic blood pressure, ACTH, cortisol, prolactin and NE as compared to the response to neutral imagery. In addition, stress imagery also increased diastolic blood pressure and plasma EPI as compared to responses to the drug cue imagery and neutral-relaxing imagery.

Conclusions

The findings indicate a significant activation of the CRF-HPA axis and noradrenergic/sympatho-adreno-medullary (SAM) system response during stress-induced and drug cue induced cocaine craving states in cocaine dependent individuals. The role of stress system activation in cocaine craving and in cocaine use is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  • Bauer LO, Kranzler HR (1994) Electroencephalographic activity and mood in cocaine-dependent outpatients: effects of cocaine cue exposure. Biol Psychiatry 36:189–197

    CAS  Google Scholar 

  • Baum A, Grunberg NE, Singer JE (1992) Biochemical measurement in the study of emotion. Psychol Sci 3:56–60

    Google Scholar 

  • Baumann MH, Gendron TM, Becketts KM, Henningfield JE, Gorelick DA, Rothman RB (1995) Effects of intravenous cocaine on plasma cortisol and prolactin in human cocaine abusers. Biol Psychiatry 38:751–755

    CAS  PubMed  Google Scholar 

  • Berger SP, Hall S, Mickalian JD, Reid MS, Crawford CA, Delucchi K, Carr K, Hall S (1996) Haloperidol antagonism of cue-elicited cocaine craving. Lancet 347:504–508

    CAS  PubMed  Google Scholar 

  • Bernardy NC, King AC, Parsons OA, Lovallo WR (1996) Altered cortisol response in sober alcoholics: an examination of contributing factors. Alcohol 13:493–498

    Article  CAS  PubMed  Google Scholar 

  • Bonate PL (ed) (2000) Analysis of pretest-posttest designs. Chapman and Hall/CRC Press, Boca Raton

  • Carter BL, Tiffany ST (1999) Meta-analysis of cue reactivity in addiction research. Addiction 94:327–340

    CAS  PubMed  Google Scholar 

  • Childress A, Hole A, Ehrman R, Robbins S, McLellan A, O'Brien C (1993) Cue reactivity and cue reactivity interventions in drug dependence. NIDA Res Monogr 137:73–95

    CAS  PubMed  Google Scholar 

  • Childress AR, Ehrman RN, McLellan AT, MacRae J, Natale M, O'Brien CP (1994) Can induced moods trigger drug-related responses in opiate abuse patients? J Subst Abuse Treat 11:17–23

    Google Scholar 

  • Chrousos GP, Gold PW (1992) The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA 267:1244–1252

    Article  CAS  PubMed  Google Scholar 

  • 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, Litt MD, Morse PA, Bauer LO, Gaupp L (1997) Alcohol cue reactivity, negative mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol 106:243–250

    CAS  PubMed  Google Scholar 

  • Di Chiara G, Imperato A (1988) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85:5274–5278

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Dunn AJ (1988) Stress-related activation of cerebral dopaminergic systems. Ann NY Acad Sci 537:188–205

    CAS  PubMed  Google Scholar 

  • Ehrman RN, Robbins SJ, Childress AR, O'Brien CP (1992) Conditioned responses to cocaine-related stimuli in cocaine abuse patients. Psychopharmacology 107:523–529

    CAS  PubMed  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

    CAS  PubMed  Google Scholar 

  • First M, Gibbon M, Spitzer R, Williams J (1995) User's Guide to the structured clinical interview for DSM-IV axis disorders (SCID-I, version 2.0)

  • Foltin RW, Haney M (2000) Conditioned effects of environmental stimuli paired with smoked cocaine in humans. Psychopharmacology 149:24–33

    CAS  PubMed  Google Scholar 

  • Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers: clinical observations. Arch Gen Psychiatry 43:107–113

    CAS  PubMed  Google Scholar 

  • Goeders NE (1997) A neuroendocrine role in cocaine reinforcement. Psychoneuroendocrinology 22:237–259

    CAS  PubMed  Google Scholar 

  • Goeders NE, Guerin GF (1994) Non-contingent electric footshock facilitates the acquisition of intravenous cocaine self-administration in rats. Psychopharmacology 114:63–70

    CAS  PubMed  Google Scholar 

  • Heesch CM, Negus BH, Keffer JH II, Snyder RW, Risser RC, Eichhorn EJ (1995) Effects of cocaine on cortisol secretion in humans. Am J Med Sci 310:61–64

    CAS  PubMed  Google Scholar 

  • Hennessey J, Levine S (1979) Stress, arousal and the pituitary-adrenal system: a psychoendocrine hypothesis. Prog Psychobiol Physiol Psychol 8:133–178

    Google Scholar 

  • Horrocks PM, Jones AF, Ratcliffe WA, Holder G, White A, Holder R, Ratcliffe JG, London DR (1990) Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females. Clin Endocrinol 32:127–134

    CAS  Google Scholar 

  • Kalivas PW, Duffy P (1989) Similar effects of daily cocaine and stress on mesocorticolimbic dopamine neurotransmission in the rat. Biol Psychiatry 25:913–928

    CAS  PubMed  Google Scholar 

  • Kang SY, Kleinman PH, Woody GE, Millman RB, Todd TC, Kemp J, Lipton DS (1991) Outcomes for cocaine abusers after once-a-week psychosocial therapy. Am J Psychiatry 148:630–635

    CAS  PubMed  Google Scholar 

  • Koob GF, Le Moal M (1997) Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Laird NM, Ware JH (1982) Random-effects models for longitudinal data. Biometrics 38:963–974

    CAS  PubMed  Google Scholar 

  • Lang PJ, Kozak MJ, Miller GA, Levin DN, McLean A Jr (1980) Emotional imagery: conceptual structure and pattern of somato-visceral response. Psychophysiology 17:179–192

    CAS  PubMed  Google Scholar 

  • Lang PJ, Levin DN, Miller GA, Kozak MJ (1983) Fear behavior, fear imagery, and the psychophysiology of emotion: the problem of affective response integration. J Abnorm Psychol 92:276–306

    CAS  PubMed  Google Scholar 

  • Litt MD, Cooney NL, Kadden RM, Gaupp L (1990) Reactivity to alcohol cues and induced moods in alcoholics. Addict Behav 15:137–146

    CAS  PubMed  Google Scholar 

  • Littell R, Milliken G, Strout W, Wolfinger R (1996) SAS system for mixed models. SAS Institute, Cary, N.C.

  • Lopez JF, Akil H, Watson SJ (1999) Role of biological and psychological factors in early development and their impact on adult life: Neural circuits mediating stress. Biol Psychiatry 46:1461–1471

    CAS  PubMed  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 

  • McLellan AT, Kushner H, Metzger D, Peters R, Smith I, Grissom G, Pettinati H, Argeriou M (1992) The fifth edition of the Addiction Severity Index. J Subst Abuse Treat 9:199–213

    Article  CAS  PubMed  Google Scholar 

  • Mello NK, Mendelson JH (1997) Cocaine's effects on neuroendocrine systems: clinical and preclinical studies. Pharmacol Biochem Behav 57:571–599

    CAS  PubMed  Google Scholar 

  • Mercer D, Carpenter G, Daley D, Patterson C, Volpicelli J (1994) Group drug counseling manual. University of Pennsylvania

  • Miczek KA, Mustschler NH (1996) Activational effects of social stress on IV cocaine self-administration in rats. Psychopharmacology 128:256–264

    CAS  PubMed  Google Scholar 

  • Miller GA, Levin DN, Kozak MJ, Cook EW III, McLean A Jr, Lang PJ (1987) Individual differences in imagery and the psychophysiology of emotion. Cognit Emot 1:367–390

    Google Scholar 

  • Miller WR, Del Boca FK (1994) Measurement of drinking behavior using the Form 90 family of instruments. J StudAlcohol 12:112–118

    CAS  Google Scholar 

  • O'Brien CP, Childress AR, Ehrman RN, Robbins SJ (1998) Conditioning factors in drug abuse: can they explain compulsion? J Psychopharmacol 12:15–22

    Google Scholar 

  • Piazza PV, Le Moal M (1996) Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids, and dopaminergic neurons. Annu Rev Pharmacol Toxicol 36:359–378

    CAS  PubMed  Google Scholar 

  • Piazza, PV, Le Moal M (1998) The role of stress in drug self-administration. Trends Pharmacol Sci 19:67–74

    CAS  PubMed  Google Scholar 

  • Piazza PV, Deminiere JM, Le Moal M, Simon H (1989) Factors that predict individual vulnerability to amphetamine self-administration. Science 245:1511–1513

    CAS  PubMed  Google Scholar 

  • Pickens RW, Johanson CE (1992) Craving: consensus of status and agenda for future research. Drug Alcohol Depend 30:127–131

    CAS  PubMed  Google Scholar 

  • Prasad BM, Sorg BA, Ulibarri C, Kalivas PW (1993) Sensitization to stress and psychostimulants: involvement of dopamine transmission versus the HPA axis. Ann NY Acad Sci 771:617–625

    Google Scholar 

  • Ramsey NF, Van Ree JM (1993) Emotional but not physical stress enhances intravenous cocaine self-administration in drug-naive rats. Brain Res 608:216–222

    CAS  PubMed  Google Scholar 

  • Robbins ST, Ehrman RN, Childress AR, O'Brien C P (1992) Using cue reactivity to screen medications for cocaine abuse: a test of amantadine hydrochloride. Addict Behav 17:491–499

    CAS  PubMed  Google Scholar 

  • Roberts DC, Koob GF, Klonoff P, Fibiger HC (1980) Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 12:781–787

    CAS  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291

    CAS  PubMed  Google Scholar 

  • Rohsenow DJ, Niaura RS, Childress AR, Abrams DB, Monti PM (1991) Cue reactivity in addictive behaviors: theoretical and treatment implications. Int J Addict 25:957–993

    CAS  Google Scholar 

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

    Google Scholar 

  • Sinha R, Parsons OA (1996) Multivariate response patterning of fear and anger. Cognit Emot 10:173–198

    Article  Google Scholar 

  • Sinha R, Lovallo WR, Parsons OA (1992) Cardiovascular differentiation of emotions. Psychosom Med 54:422–435

    CAS  PubMed  Google Scholar 

  • Sinha R, Catapano D, O'Malley SS (1999) Stress-induced craving and stress response in cocaine dependent individuals. Psychopharmacology 142:343–351

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Sofuoglu M, Nelson D, Babb DA, Hatsukami DK (2001) Intravenous cocaine increases plasma epinephrine and norepinephrine in humans. Pharmacol Biochem Behav 68:455–459

    Article  CAS  PubMed  Google Scholar 

  • Stewart J (2000) Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiatr Neurosci 25:125–136

    CAS  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

    CAS  PubMed  Google Scholar 

  • Taylor JR, Robbins TW (1984) Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens. Psychopharmacology 84:405–412

    CAS  PubMed  Google Scholar 

  • Thierry AM, Tassin JP, Blanc G, Glowinski J (1976) Selective activation of mesocortical DA system by stress. Nature 263:242–244

    Google Scholar 

  • Tiffany ST (1990) A cognitive model of drug urges and drug use behavior: role of automatic and nonautomatic processes. Psychol Rev 97:147–168

    CAS  PubMed  Google Scholar 

  • Venables WN, Ripley BD (1997) Modern applied statistics with S-PLUS (1st edn). Springer, New York

Download references

Acknowledgements

This study was supported in part by grants R01-DA11077 (Sinha), K02-DA00397 (Malison), K12-DA14038 (Sinha), P50-DA05130 and M01-RR00125 from the National Institutes of Health, Bethesda, Md., USA, a NARSAD Independent Investigator Award (Malison) and a Donoghue Medical Research Foundation Award (Malison). We wish to 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 and those at the Laboratory on the Biology of Addictive Diseases at Rockefeller University for their assistance in completing the study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rajita Sinha.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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 170, 62–72 (2003). https://doi.org/10.1007/s00213-003-1525-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1525-8

Keywords

Navigation