Skip to main content
SpringerLink
Log in

Yohimbine administration and cue-reactivity in cocaine-dependent individuals

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

Abstract

Rationale

Preclinical studies suggest that stress potentiates cue-induced cocaine seeking and that this effect is more pronounced in females. These findings have not been characterized in clinical populations.

Objectives

The objectives of this study were to examine the impact a pharmacological stressor, alpha-2 adrenergic receptor antagonist yohimbine, on the subjective, endocrine, and physiologic responses to drug-paired cues cocaine-dependent men and women.

Methods

In a double-blind placebo-controlled cross-over study, cocaine-dependent men (n = 32), cocaine-dependent women (n = 30), control men (n = 32), and control women (n = 25) received either yohimbine or placebo prior to two cocaine cue exposure sessions.

Results

Yohimbine increased ratings of anxiety both before (p < 0.001) and after (p = 0.035) cues, and the post-cue increase in anxiety was more pronounced in women (p = 0.001). Yohimbine also significantly increased craving, compared with placebo (p < 0.05), following the cue presentation, and this effect was greater in women than men (gender by treatment interaction; p = 0.006). Yohimbine also increased salivary cortisol (p < 0.001) and dehydroepiandrosterone (p = 0.003) levels, regardless of diagnostic group. Women had a significantly greater heart rate response following yohimbine as compared with men (p < 0.001).

Conclusions

Stress may increase the salience of cocaine cues for cocaine-dependent women as compared with men. This suggests gender differences in vulnerability to craving and relapse under stressful conditions.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Alleweireldt AT, Weber SM, Neisewander JL (2001) Passive exposure to a contextual discriminative stimulus reinstates cocaine-seeking behavior in rats. Pharmacol, Biochem Behav 69:555–560

    Article  CAS  Google Scholar 

  • Anker JJ, Carroll ME (2010) Sex differences in the effects of allopregnanolone on yohimbine-induced reinstatement of cocaine seeking in rats. Drug Alcohol Depend 107:264–267

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Back SE, Brady KT, Jackson JL, Salstrom S, Zinzow H (2005) Gender differences in stress reactivity among cocaine-dependent individuals. Psychopharmacology 180:169–176

    Article  PubMed  CAS  Google Scholar 

  • Banna KM, Back SE, Do P, See RE (2010) Yohimbine stress potentiates conditioned cue-induced reinstatement of heroin-seeking in rats. Behav Brain Res 208:144–208

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bhattacharya SK, Clow A, Przyborowska A, Halket J, Glover V, Sandler M (1991) Effect of aromatic amino acids, pentylenetetrazole and yohimbine on isatin and tribulin activity in rat brain. Neurosci Lett 132:44–46

    Article  PubMed  CAS  Google Scholar 

  • Brady KT, McRae AL, Moran-Santa Maria MM, DeSantis SM, Simpson AN, Waldrop AE, Back SE, Kreek MJ (2009) Response to corticotropin-releasing hormone infusion in cocaine-dependent individuals. Arch Gen Psychiatry 66:422–430

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Buffalari DM, See RE (2009) Footshock stress potentiates cue-induced cocaine-seeking in an animal model of relapse. Physiol Behav 98:614–617

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Buffalari DM, Baldwin CK, Feltenstein MW, See RE (2012) Corticotrophin releasing factor (CRF) induced reinstatement of cocaine seeking in male and female rats. Physiol Behav 105:209–214

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Buydens-Branchey L, Branchey M, Hudson J, Dorota Majewska M (2002) Perturbations of plasma cortisol and DHEA-S following discontinuation of cocaine use in cocaine addicts. Psychoneuroendocrinology 27:83–97

    Article  PubMed  CAS  Google Scholar 

  • Camp DM, Robinson TE (1988) Susceptibility to sensitization. I. Sex differences in the enduring effects of chronic d-amphetamine treatment on locomotion, stereotyped behavior and brain monoamines. Behav Brain Res 30:55–68

    Article  PubMed  CAS  Google Scholar 

  • Childress AR, McLellan AT, O'Brien CP (1986) Conditioned responses in a methadone population. A comparison of laboratory, clinic, and natural settings. J Subst Abuse Treat 3:173–179

    Article  PubMed  CAS  Google Scholar 

  • Coffey SF, Saladin ME, Drobes DJ, Brady KT, Dansky BS, Kilpatrick DG (2002) Trauma and substance cue reactivity in individuals with comorbid posttraumatic stress disorder and cocaine or alcohol dependence. Drug Alcohol Depend 65:115–127

    Article  PubMed  Google Scholar 

  • Erb S, Shaham Y, Stewart J (1996) Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period. Psychopharmacology (Berl) 128:408–412

    Article  CAS  Google Scholar 

  • Feltenstein MW, See RE (2006) Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine. Behav Brain Res 174:1–8

    Article  PubMed  CAS  Google Scholar 

  • Feltenstein MW, Henderson AR, See RE (2011) Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. Psychopharmacology (Berl) 216:53–62

    Article  CAS  Google Scholar 

  • First MB, Frances AJ, Pincus HA, Vettorello N, Davis WW (1994) DSM-IV in progress. Changes in substance-related, schizophrenic, and other primarily adult disorders. Hosp Community Psychiatry 45:18–20

    PubMed  CAS  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

    Article  CAS  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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fox HC, Morgan PT, Sinha R (2014) Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals. Neuropsychopharmacology (in press)

  • Harris GC, Aston-Jones G (1993) Beta-adrenergic antagonists attenuate withdrawal anxiety in cocaine- and morphine-dependent rats. Psychopharmacology (Berl) 113:131–136

    Article  CAS  Google Scholar 

  • Holly EN, Shimamoto A, Debold JF, Miczek KA (2012) Sex differences in behavioral and neural cross-sensitization and escalated cocaine taking as a result of episodic social defeat stress in rats. Psychopharmacology 224:179–188

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Jobes ML, Ghitza UE, Epstein DH, Phillips KA, Heishman SJ, Preston KL (2011) Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology 218:83–88

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Liu X, Weiss F (2002) Additive effect of stress and drug cues on reinstatement of ethanol seeking: exacerbation by history of dependence and role of concurrent activation of corticotropin-releasing factor and opioid mechanisms. J Neurosci: Off J Soc Neurosci 22:7856–7861

    CAS  Google Scholar 

  • Maccari S, Mormede P, Piazza PV, Simon H, Angelucci L, Le Moal M (1992a) Hippocampal type I and type II corticosteroid receptors are modulated by central noradrenergic systems. Psychoneuroendocrinology 17:103–112

    Article  PubMed  CAS  Google Scholar 

  • Maccari S, Piazza PV, Rouge-Pont F, Angelucci L, Simon H, le Moal M (1992b) Noradrenergic regulation of type-I and type-II corticosteroid receptors in amygdala and hypothalamus. Brain Res 587:313–318

    Article  PubMed  CAS  Google Scholar 

  • McDougle CJ, Black JE, Malison RT, Zimmermann RC, Kosten TR, Heninger GR, Price LH (1994) Noradrenergic dysregulation during discontinuation of cocaine use in addicts. Arch Gen Psychiatry 51:713–719

    Article  PubMed  CAS  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 Mental Dis 184:616–622

    Article  CAS  Google Scholar 

  • Millan MJ, Newman-Tancredi A, Audinot V, Cussac D, Lejeune F, Nicolas JP, Coge F, Galizzi JP, Boutin JA, Rivet JM, Dekeyne A, Gobert A (2000) Agonist and antagonist actions of yohimbine as compared to fluparoxan at alpha(2)-adrenergic receptors (AR)s, serotonin (5-HT)(1A), 5-HT(1B), 5-HT(1D) and dopamine D(2) and D(3) receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states. Synapse 35:79–95

    Article  PubMed  CAS  Google Scholar 

  • O'Carroll RE, Drysdale E, Cahill L, Shajahan P, Ebmeier KP (1999) Stimulation of the noradrenergic system enhances and blockade reduces memory for emotional material in man. Psychol Med 29:1083–1088

    Article  PubMed  Google Scholar 

  • Patterson HD, Thompson R (1971) Recovery of inter-block information when block sizes are unequal. Biometrika 58:545–564

    Article  Google Scholar 

  • Preston KL, Epstein DH (2011) Stress in the daily lives of cocaine and heroin users: relationship to mood, craving, relapse triggers, and cocaine use. Psychopharmacology (Berl) 218:29–37

    Article  CAS  Google Scholar 

  • Rudoy CA, Van Bockstaele EJ (2007) Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats. Prog Neuro-psychopharmacol Biol Psychiatry 31:1119–1129

    Article  CAS  Google Scholar 

  • Saladin ME, Drobes DJ, Coffey SF, Dansky BS, Brady KT, Kilpatrick DG (2003) PTSD symptom severity as a predictor of cue-elicited drug craving in victims of violent crime. Addict Behav 28:1611–1629

    Article  PubMed  Google Scholar 

  • Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC (1998) The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 59(Suppl 20):22–33, quiz 34–57

    PubMed  Google Scholar 

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

    Article  PubMed  CAS  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

    Article  CAS  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

    Article  CAS  Google Scholar 

  • Sinha R, Fox H, Hong KI, Sofuoglu M, Morgan PT, Bergquist KT (2007) Sex steroid hormones, stress response, and drug craving in cocaine-dependent women: implications for relapse susceptibility. Exp Clin Psychopharmacol 15:445–452

    Article  PubMed  CAS  Google Scholar 

  • Sobell LC, Sobell MB (1992) Timeline follow-back: A technique for assessing self-reported ethanol consumption. In: Allen J, Litten RZ (eds) Measuring alcohol consumption: Psychological and Biological Methods. Humana Press, Totowa, NJ, pp 41–72

    Chapter  Google Scholar 

  • Stockwell T, Murphy D, Hodgson R (1983) The severity of alcohol dependence questionnaire: its use, reliability and validity. Br J Addict 78:145–155

    Article  PubMed  CAS  Google Scholar 

  • Swann AC, Birnbaum D, Jagar AA, Dougherty DM, Moeller FG (2005) Acute yohimbine increases laboratory-measured impulsivity in normal subjects. Biol Psychiatry 57:1209–1211

    Article  PubMed  CAS  Google Scholar 

  • Waldrop AE, Price KL, Desantis SM, Simpson AN, Back SE, McRae AL, Spratt EG, Kreek MJ, Brady KT (2009) Community-dwelling cocaine-dependent men and women respond differently to social stressors versus cocaine cues. Psychoneuroendocrinology

Download references

Conflict of interest

Moran-Santa Maria, Baker, and Ramakrishnan declare no conflict of interest. Kathleen Brady is a Consultant of AstraZeneca Pharmaceuticals. Aimee McRae is provided with a separate NIH grant by Forest Pharmaceuticals.

Funding

This work was supported by the National Institutes of Health, National Institute on Drug Abuse and the Office of Research on Women’s Health P50DA016511, National Institute of Child Health and Human Development K12 HD055885, and National Center for Advancing Translational Sciences UL1TR000062.

Author information

Authors and Affiliations

  1. Clinical Neuroscience Division, Department of Psychiatry and Behavioral Neurosciences, Medical University of South Carolina, 125 Doughty Street, Charleston, SC, 29425, USA

    Megan M. Moran-Santa Maria, Aimee McRae-Clark & Kathleen T. Brady

  2. Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA

    Nathaniel L. Baker & Viswanathan Ramakrishnan

  3. Ralph H Johnson, VAMC, Charleston, SC, 29401, USA

    Kathleen T. Brady

Authors
  1. Megan M. Moran-Santa Maria
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aimee McRae-Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nathaniel L. Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viswanathan Ramakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kathleen T. Brady
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Megan M. Moran-Santa Maria.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moran-Santa Maria, M.M., McRae-Clark, A., Baker, N.L. et al. Yohimbine administration and cue-reactivity in cocaine-dependent individuals. Psychopharmacology 231, 4157–4165 (2014). https://doi.org/10.1007/s00213-014-3555-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3555-9

Keywords

Search

Navigation