Skip to main content

Advertisement

SpringerLink
Log in

Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans

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

Abstract

Rationale

Chronic drug use has been associated with increased impulsivity and maladaptive behaviour, but the underlying mechanisms of this impairment remain unclear. We investigated the ability to adapt behaviour according to changes in reward contingencies, using a probabilistic reversal-learning task, in chronic drug users and controls.

Materials and methods

Five groups were compared: chronic amphetamine users (n = 30); chronic cocaine users (n = 27); chronic opiate users (n = 42); former drug users of psychostimulants and opiates (n = 26); and healthy non-drug-taking control volunteers (n = 25). Participants had to make a forced choice between two alternative stimuli on each trial to acquire a stimulus–reward association on the basis of degraded feedback and subsequently to reverse their responses when the reward contingencies changed.

Results

Chronic cocaine users demonstrated little behavioural change in response to the change in reward contingencies, as reflected by perseverative responding to the previously rewarded stimulus. Perseverative responding was observed in cocaine users regardless of whether they completed the reversal stage successfully. Task performance in chronic users of amphetamines and opiates, as well as in former drug users, was not measurably impaired.

Conclusion

Our findings provide convincing evidence for response perseveration in cocaine users during probabilistic reversal-learning. Pharmacological differences between amphetamine and cocaine, in particular their respective effects on the 5-HT system, may account for the divergent task performance between the two psychostimulant user groups. The inability to reverse responses according to changes in reinforcement contingencies may underlie the maladaptive behaviour patterns observed in chronic cocaine users but not in chronic users of amphetamines or opiates.

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

Similar content being viewed by others

References

  • Annett LE, Ridley RM, Gamble SJ, Baker HF (1983) Behavioral effects of intracerebral amphetamine in the marmoset. Psychopharmacology 81:18–23

    Article  PubMed  CAS  Google Scholar 

  • Arnsten AFT (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci 2:436–447

    Article  Google Scholar 

  • Beck AT, Steer RA, Brown GK (1996) Manual for Beck Depression Inventory-II. Psychological Corporation, San Antonio, TX, USA

    Google Scholar 

  • Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ (2006) Neurochemical modulation of response inhibition and probabilistic learning in humans. Science 311:861–863

    Article  PubMed  CAS  Google Scholar 

  • Clark L, Roiser JP, Cools R, Rubinsztein DC, Sahakian BJ, Robbins TW (2005) Stop signal response inhibition is not modulated by tryptophan depletion or the serotonin transporter polymorphism in healthy volunteers: implications for the 5-HT theory of impulsivity. Psychopharmacology 182:570–578

    Article  PubMed  CAS  Google Scholar 

  • Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 304:878–880

    Article  PubMed  CAS  Google Scholar 

  • Cools R, Clark L, Owen AM, Robbins TW (2002) Defining the neural mechanisms of probabilistic reversal learning using event-related functional magnetic resonance imaging. J Neurosci 22:4563–4567

    PubMed  CAS  Google Scholar 

  • Daw ND, Kakade S, Dayan P (2002) Opponent interactions between serotonin and dopamine. Neural netw 15:603–616

    Article  PubMed  Google Scholar 

  • de la Torre R, Farre M, Navarro M, Pacifici R, Zuccaro P, Pichini S (2004) Clinical pharmacokinetics of amfetamine and related substances—monitoring in conventional and non-conventional matrices. Clin pharmacokinet 43:157–185

    Article  PubMed  Google Scholar 

  • De Win MML, Reneman L, Jager G, Vlieger EJP, Olabarriaga SD, Lavini C, Bisschops I, Majoie CBLM, Booij J, den Heeten GJ, Van den Brink W (2007) A prospective cohort study on sustained effects of low-dose ecstasy use on the brain in new ecstasy users. Neuropsychopharmacology 32:458–470

    Article  PubMed  CAS  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 U S A 85:5274–5278

    Article  PubMed  Google Scholar 

  • Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489

    Article  PubMed  CAS  Google Scholar 

  • Evers EAT, Cools R, Clark L, van der Veen FM, Jolles J, Sahakian BJ, Robbins TW (2005) Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning. Neuropsychopharmacology 30:1138–1147

    Article  PubMed  CAS  Google Scholar 

  • Filip M, Frankowska M, Zaniewska M, Golda A, Przegalinski E (2005) The serotonergic system and its role in cocaine addiction. Pharmacol Rep 57:685–700

    PubMed  CAS  Google Scholar 

  • Fillmore MT, Rush CR (2002) Impaired inhibitory control of behavior in chronic cocaine users. Drug Alcohol Depend 66:265–273

    Article  PubMed  Google Scholar 

  • Fillmore MT, Rush CR (2006) Polydrug abusers display impaired discrimination-reversal learning in a model of behavioural control. J Psychopharmacol 20:24–32

    Google Scholar 

  • Fillmore MT, Rush CR, Hays L (2006) Acute effects of cocaine in two models of inihibitory control: implications of non-linear dose effects. Addiction 101:1323–1332

    Article  PubMed  Google Scholar 

  • Forman SD, Dougherty GG, Casey BJ, Siegle GJ, Braver TS, Barch DM, Stenger VA, Wick-Hull C, Pisarov LA, Lorensen E (2004) Opiate addicts lack error-dependent activation of rostral anterior cingulate. Biol Psychiat 55:531–537

    Article  PubMed  CAS  Google Scholar 

  • Garavan H, Lingford-Hughes A, Jones T, Morris P, Rothwell J, Williams S (2005) Overview of the application of functional neuroimaging to studying addiction: with particular reference to cognitive neuroscience investigations. UK Government Foresight Report.

  • Gossop M, Darke S, Griffiths P, Hando J, Powis B, Hall W, Strang J (1995) The severity of dependence scale (SDS): Psychometric properties of the SDS in English and Australian samples of heroin, cocaine and amphetamine users. Addiction 90:607–614

    Article  PubMed  CAS  Google Scholar 

  • Gouzoulis-Mayfrank E, Daumann J (2006) Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage. Addiction 101:348–361

    Article  PubMed  CAS  Google Scholar 

  • Graveland GA, Williams RS, Difiglia M (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntingtons-disease. Science 227:770–773

    Article  PubMed  CAS  Google Scholar 

  • Hester R, Garavan H (2004) Executive dysfunction in cocaine addiction: evidence for discordant frontal, cingulate, and cerebellar activity. J Neurosci 24:11017–11022

    Article  PubMed  CAS  Google Scholar 

  • Hornak J, O’Doherty J, Bramham J, Rolls ET, Morris RG, Bullock PR, Polkey CE (2004) Reward-related reversal learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in humans. J cogn neurosci 16:463–478

    Article  PubMed  CAS  Google Scholar 

  • Howell DC (1997) Statistical methods for psychology. Duxbury, London

    Google Scholar 

  • Howell LL, Hoffman JM, Votaw JR, Landrum AM, Wilcox KM, Lindsey KP (2002) Cocaine-induced brain activation determined by positron emission tomography neuroimaging in conscious rhesus monkeys. Psychopharmacology 159:154–160

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146:373–390

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Olausson P, De La Garza IR, Taylor JR (2002) Impairments of reversal learning and response perseveration after repeated, intermittent cocaine administrations to monkeys. Neuropsychopharmacology 26:183–190

    Article  PubMed  CAS  Google Scholar 

  • Johanson CE, Fischman MW (1989) The pharmacology of cocaine related to its abuse. Pharmacol Rev 41:3–52

    PubMed  CAS  Google Scholar 

  • Kaufman JN, Ross TJ, Stein EA, Garavan H (2003) Cingulate hypoactivity in cocaine users during a GO–NOGO task as revealed by event-related functional magnetic resonance imaging. J Neurosci 23:7839–7843

    PubMed  CAS  Google Scholar 

  • Kuczenski R, Segal DS, Cho AK, Melega W (1995) Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J Neurosci 15:1308–1317

    PubMed  CAS  Google Scholar 

  • Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68:2032–2037

    Article  PubMed  CAS  Google Scholar 

  • Lange KW, Sahakian BJ, Quinn NP, Marsden CD, Robbins TW (1995) Comparison of executive and visuospatial memory function in Huntington’s disease and dementia of Alzheimer type matched for degree of dementia. J Neurol Neurosurg Psychiatry 8:598–606

    Google Scholar 

  • Lawrence AD, Sahakian BJ, Rogers RD, Hodges JR, Robbins TW (1999) Discrimination, reversal, and shift learning in Huntington’s disease: mechanisms of impaired response selection. Neuropsychologia 37:1359–1374

    Article  PubMed  CAS  Google Scholar 

  • Lee B, Groman S, London ED, Jentsch JD (2007) Dopamine D2/D3 dopamine receptors play a specific role in reversal of a learned visual discrimination in monkeys. Neuropsychopharmacology 32(10):2125–2134

    Article  PubMed  CAS  Google Scholar 

  • Lee TMC, Zhou WH, Luo XJ, Yuen KSL, Ruan XZ, Weng XC (2005) Neural activity associated with cognitive regulation in heroin users: a fMRI study. Neurosci lett 382:211–216

    Article  PubMed  CAS  Google Scholar 

  • London ED, Simon SL, Berman SM, Mandelkern MA, Lichtman AM, Bramen J, Shinn AK, Miotto K, Learn J, Dong Y, Matochik JA, Kurian V, Newton T, Woods R, Rawson R, Ling W (2004) Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. Arch Gen Psychiatry 61:73–84

    Article  PubMed  Google Scholar 

  • Lyons D, Friedman DP, Nader MA, Porrino LJ (1996) Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J Neurosci 16:1230–1238

    PubMed  CAS  Google Scholar 

  • Lyvers M (2006) Recreational ecstasy use and the neurotoxic potential of MDMA: current status of the controversy and methodological issues. Drug Alcohol Rev 25:269–276

    Article  PubMed  Google Scholar 

  • McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM (2005) The nature, time course and severity of methamphetamine withdrawal. Addiction 100:1320–1329

    Article  PubMed  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  PubMed  CAS  Google Scholar 

  • Monterosso JR, Aron AR, Cordova X, Xu J, London ED (2005) Deficits in response inhibition associated with chronic methamphetamine abuse. Drug Alcohol Depend 79:273–277

    Article  PubMed  Google Scholar 

  • Murphy FC, Michael A, Robbins TW, Sahakian BJ (2003) Neuropsychological impairment in patients with major depressive disorder: the effects of feedback on task performance. Psychol Med 33:455–467

    Article  PubMed  CAS  Google Scholar 

  • Nelson HE (1982) National adult reading test manual. NFER-Nelson, Windsor (UK)

    Google Scholar 

  • Ornstein TJ, Iddon JL, Baldacchino AM, Sahakian BJ, London M, Everitt BJ, Robbins TW (2000) Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers. Neuropsychopharmacology 23:113–126

    Article  PubMed  CAS  Google Scholar 

  • Patton JH, Stanford MS, Barratt ES (1995) Factor structure of the Barratt Impulsiveness Scale. J Clin Psychol 51:768–774

    Article  PubMed  CAS  Google Scholar 

  • Peat MA, Warren PF, Bakhit C, Gibb JW (1985) The acute effects of methamphetamine, amphetamine and p-chloroamphetamine on the cortical serotonergic system of the rat brain: evidence for differences in the effects of methamphetamine and amphetamine. Eur j pharmacol 116:11–16

    Article  PubMed  CAS  Google Scholar 

  • Peltier RL, Li DH, Lytle D, Taylor CM, Emmett-Oglesby MW (1996) Chronic d-amphetamine or methamphetamine produces cross-tolerance to the discriminative and reinforcing stimulus effects of cocaine. J Pharmacol Exp Ther 277:212–218

    PubMed  CAS  Google Scholar 

  • Porrino LJ, Lyons D (2000) Orbital and medial prefrontal cortex and psychostimulant abuse: studies in animal models. Cereb Cortex 10:326–333

    Article  PubMed  CAS  Google Scholar 

  • Porrino LJ, Smith HR, Nader MA, Beveridge TJR (2007) The effects of cocaine: a shifting target over the course of addiction. Prog neuro-psychopharmacol biol psychiatry 31:1593–1600

    Article  CAS  Google Scholar 

  • Ricaurte GA, Fuller RW, Perry KW, Seiden LS, Schuster CR (1983) Fluoxetine increases long-lasting neostriatal dopamine depletion after administration of d-methamphetamine and d-amphetamine. Neuropharmacology 22:1165–1169

    Article  PubMed  CAS  Google Scholar 

  • Ridley RM, Haystead TAJ, Baker HF (1981a) An analysis of visual object reversal-learning in the marmoset after amphetamine and haloperidol. Pharmacol Biochem Behav 14:345–351

    Article  PubMed  CAS  Google Scholar 

  • Ridley RM, Haystead TAJ, Baker HF (1981b) An analysis of visual object reversal learning in the marmoset after amphetamine and haloperidol. Pharmacol Biochem Behav 14:345–351

    Article  PubMed  CAS  Google Scholar 

  • Rolls ET (2000) The orbitofrontal cortex and reward. Cereb Cortex 10:284–294

    Article  PubMed  CAS  Google Scholar 

  • Rolls ET, Hornak J, Wade D, Mcgrath J (1994) Emotion-related learning in patients with social and emotional changes associated with frontal-lobe damage. J Neurol Neurosurg Psychiatry 57:1518–1524

    Article  PubMed  CAS  Google Scholar 

  • Schoenbaum G, Saddoris MP, Ramus SJ, Shaham Y, Setlow B (2004) Cocaine-experienced rats exhibit learning deficits in a task sensitive to orbitofrontal cortex lesions. Eur J Neurosci 19:1997–2002

    Article  PubMed  Google Scholar 

  • Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593–1599

    Article  PubMed  CAS  Google Scholar 

  • Segal DS, Kuczenski R, O’Neil ML, Melega WP, Cho AK (2003) Escalating dose methamphetamine pretreatment alters the behavioral and neurochemical profiles associated with exposure to a high-dose methamphetamine binge. Neuropsychopharmacology 28:1730–1740

    Article  PubMed  CAS  Google Scholar 

  • Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639–676

    Article  PubMed  CAS  Google Scholar 

  • Sekine Y, Ouchi Y, Takei N, Yoshikawa E, Nakamura K, Futatsubashi M, Okada H, Minabe Y, Suzuki K, Iwata Y, Tsuchiya KJ, Tsukada H, Iyo M, Mori N (2006) Brain serotonin transporter density and aggression in abstinent methamphetamine abusers. Arch Gen Psychiatry 63:90–100

    Article  PubMed  CAS  Google Scholar 

  • Sofuoglu M, Dudish-Poulsen S, Poling J, Mooney M, Hatsukami DK (2005) The effect of individual cocaine withdrawal symptoms on outcomes in cocaine users. Addict Behav 30:1125–1134

    Article  PubMed  Google Scholar 

  • Swainson R, Rogers RD, Sahakian BJ, Summers BA, Polkey CE, Robbins TW (2000) Probabilistic learning and reversal deficits in patients with Parkinson’s disease or frontal or temporal lobe lesions: possible adverse effects of dopaminergic medication. Neuropsychologia 38:596–612

    Article  PubMed  CAS  Google Scholar 

  • U.K.Department of Health (1999) Drug misuse and dependence—guidelines on clinical management. The Stationery Office, Norwich,UK

    Google Scholar 

  • United Nations Office on Drugs and Crime (2007) World drug report 2007. United Nations Office on Drugs and Crime (UNODC), New York, NY, USA

    Google Scholar 

  • Verdejo-Garcia AJ, Lopez-Torrecillas F, Aguilar de Arcos F, Perez-Garcia M (2005) Differential effects of MDMA, cocaine, and cannabis use severity on distinctive components of the executive functions in polysubstance users: A multiple regression analysis. Addict Behav 30:89–101

    Article  PubMed  Google Scholar 

  • Verdejo-Garcia AJ, Perales JC, Perez-Garcia M (2007) Cognitive impulsivity in cocaine and heroin polysubstance abusers. Addict Behav 32:950–966

    Article  PubMed  Google Scholar 

  • White FJ, Kalivas PW (1998) Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend 51:141–153

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors want to thank the volunteers who took part in this study, particularly to those who aided with recruitment, and members of Narcotics Anonymous. This work was funded by a Wellcome Trust Programme Grant (no. 076274/Z/04/Z) to Professors TW Robbins, BJ Everitt, BJ Sahakian and Dr. AC Roberts and carried out within the University of Cambridge Behavioural and Clinical Neurosciences Institute (supported by a joint award from the MRC and the Wellcome Trust). Data acquisition was supported in part by Clinical Pharmacology & Discovery Medicine, GlaxoSmithKline R&D. KD Ersche holds the Betty Behrens Research Fellowship from Clare Hall College, Cambridge (U.K.) and was supported by the Fund for Addenbrooke’s and the Grindley Fund. JP Roiser held an MRC Research Studentship and is currently a recipient of the Raymond Way Fellowship at the Institute of Neurology, University College London (UK).

Author information

Authors and Affiliations

  1. Department of Psychiatry, Brain Mapping Unit, School of Clinical Medicine, University of Cambridge, Box 255, Addenbrooke’s Hospital, Cambridge, UK

    Karen D. Ersche

  2. Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, UK

    Karen D. Ersche, Jonathan P. Roiser, Trevor W. Robbins & Barbara J. Sahakian

  3. Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Box 189, Addenbrooke’s Hospital, Cambridge, UK

    Jonathan P. Roiser & Barbara J. Sahakian

  4. Department of Experimental Psychology, University of Cambridge, Downing Street, Cambridge, UK

    Trevor W. Robbins

  5. Institute of Cognitive Neuroscience, 17 Queen Square, London, WC1N 3AR, UK

    Jonathan P. Roiser

Authors
  1. Karen D. Ersche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan P. Roiser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Trevor W. Robbins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Barbara J. Sahakian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karen D. Ersche.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ersche, K.D., Roiser, J.P., Robbins, T.W. et al. Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans. Psychopharmacology 197, 421–431 (2008). https://doi.org/10.1007/s00213-007-1051-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-007-1051-1

Keywords

Search

Navigation