Advertisement

Psychopharmacology

, Volume 197, Issue 3, pp 421–431 | Cite as

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

  • Karen D. ErscheEmail author
  • Jonathan P. Roiser
  • Trevor W. Robbins
  • Barbara J. Sahakian
Original Investigation

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.

Keywords

Cocaine Amphetamines Opiates Probabilistic reversal learning Serotonin Perseveration 

Notes

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).

References

  1. Annett LE, Ridley RM, Gamble SJ, Baker HF (1983) Behavioral effects of intracerebral amphetamine in the marmoset. Psychopharmacology 81:18–23PubMedCrossRefGoogle Scholar
  2. Arnsten AFT (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci 2:436–447CrossRefGoogle Scholar
  3. Beck AT, Steer RA, Brown GK (1996) Manual for Beck Depression Inventory-II. Psychological Corporation, San Antonio, TX, USAGoogle Scholar
  4. Chamberlain SR, Muller U, Blackwell AD, Clark L, Robbins TW, Sahakian BJ (2006) Neurochemical modulation of response inhibition and probabilistic learning in humans. Science 311:861–863PubMedCrossRefGoogle Scholar
  5. 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 182:570–578PubMedCrossRefGoogle Scholar
  6. Clarke HF, Dalley JW, Crofts HS, Robbins TW, Roberts AC (2004) Cognitive inflexibility after prefrontal serotonin depletion. Science 304:878–880PubMedCrossRefGoogle Scholar
  7. 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 22:4563–4567PubMedGoogle Scholar
  8. Daw ND, Kakade S, Dayan P (2002) Opponent interactions between serotonin and dopamine. Neural netw 15:603–616PubMedCrossRefGoogle Scholar
  9. 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 43:157–185PubMedCrossRefGoogle Scholar
  10. 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 32:458–470PubMedCrossRefGoogle Scholar
  11. 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 85:5274–5278PubMedCrossRefGoogle Scholar
  12. Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489PubMedCrossRefGoogle Scholar
  13. 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 30:1138–1147PubMedCrossRefGoogle Scholar
  14. Filip M, Frankowska M, Zaniewska M, Golda A, Przegalinski E (2005) The serotonergic system and its role in cocaine addiction. Pharmacol Rep 57:685–700PubMedGoogle Scholar
  15. Fillmore MT, Rush CR (2002) Impaired inhibitory control of behavior in chronic cocaine users. Drug Alcohol Depend 66:265–273PubMedCrossRefGoogle Scholar
  16. Fillmore MT, Rush CR (2006) Polydrug abusers display impaired discrimination-reversal learning in a model of behavioural control. J Psychopharmacol 20:24–32Google Scholar
  17. Fillmore MT, Rush CR, Hays L (2006) Acute effects of cocaine in two models of inihibitory control: implications of non-linear dose effects. Addiction 101:1323–1332PubMedCrossRefGoogle Scholar
  18. 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 55:531–537PubMedCrossRefGoogle Scholar
  19. 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.Google Scholar
  20. 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 90:607–614PubMedCrossRefGoogle Scholar
  21. Gouzoulis-Mayfrank E, Daumann J (2006) Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: how strong is the evidence for persistent brain damage. Addiction 101:348–361PubMedCrossRefGoogle Scholar
  22. Graveland GA, Williams RS, Difiglia M (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntingtons-disease. Science 227:770–773PubMedCrossRefGoogle Scholar
  23. Hester R, Garavan H (2004) Executive dysfunction in cocaine addiction: evidence for discordant frontal, cingulate, and cerebellar activity. J Neurosci 24:11017–11022PubMedCrossRefGoogle Scholar
  24. 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 16:463–478PubMedCrossRefGoogle Scholar
  25. Howell DC (1997) Statistical methods for psychology. Duxbury, LondonGoogle Scholar
  26. 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 159:154–160PubMedCrossRefGoogle Scholar
  27. Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology 146:373–390PubMedCrossRefGoogle Scholar
  28. 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 26:183–190PubMedCrossRefGoogle Scholar
  29. Johanson CE, Fischman MW (1989) The pharmacology of cocaine related to its abuse. Pharmacol Rev 41:3–52PubMedGoogle Scholar
  30. 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 23:7839–7843PubMedGoogle Scholar
  31. 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 15:1308–1317PubMedGoogle Scholar
  32. Kuczenski R, Segal DS (1997) Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. J Neurochem 68:2032–2037PubMedCrossRefGoogle Scholar
  33. 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 8:598–606Google Scholar
  34. 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 37:1359–1374PubMedCrossRefGoogle Scholar
  35. 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):2125–2134PubMedCrossRefGoogle Scholar
  36. 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 382:211–216PubMedCrossRefGoogle Scholar
  37. 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 61:73–84PubMedCrossRefGoogle Scholar
  38. Lyons D, Friedman DP, Nader MA, Porrino LJ (1996) Cocaine alters cerebral metabolism within the ventral striatum and limbic cortex of monkeys. J Neurosci 16:1230–1238PubMedGoogle Scholar
  39. Lyvers M (2006) Recreational ecstasy use and the neurotoxic potential of MDMA: current status of the controversy and methodological issues. Drug Alcohol Rev 25:269–276PubMedCrossRefGoogle Scholar
  40. McGregor C, Srisurapanont M, Jittiwutikarn J, Laobhripatr S, Wongtan T, White JM (2005) The nature, time course and severity of methamphetamine withdrawal. Addiction 100:1320–1329PubMedCrossRefGoogle Scholar
  41. 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 9:199–213PubMedCrossRefGoogle Scholar
  42. Monterosso JR, Aron AR, Cordova X, Xu J, London ED (2005) Deficits in response inhibition associated with chronic methamphetamine abuse. Drug Alcohol Depend 79:273–277PubMedCrossRefGoogle Scholar
  43. 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 33:455–467PubMedCrossRefGoogle Scholar
  44. Nelson HE (1982) National adult reading test manual. NFER-Nelson, Windsor (UK)Google Scholar
  45. 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 23:113–126PubMedCrossRefGoogle Scholar
  46. Patton JH, Stanford MS, Barratt ES (1995) Factor structure of the Barratt Impulsiveness Scale. J Clin Psychol 51:768–774PubMedCrossRefGoogle Scholar
  47. 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 116:11–16PubMedCrossRefGoogle Scholar
  48. 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 277:212–218PubMedGoogle Scholar
  49. Porrino LJ, Lyons D (2000) Orbital and medial prefrontal cortex and psychostimulant abuse: studies in animal models. Cereb Cortex 10:326–333PubMedCrossRefGoogle Scholar
  50. 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 31:1593–1600CrossRefGoogle Scholar
  51. 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 22:1165–1169PubMedCrossRefGoogle Scholar
  52. Ridley RM, Haystead TAJ, Baker HF (1981a) An analysis of visual object reversal-learning in the marmoset after amphetamine and haloperidol. Pharmacol Biochem Behav 14:345–351PubMedCrossRefGoogle Scholar
  53. Ridley RM, Haystead TAJ, Baker HF (1981b) An analysis of visual object reversal learning in the marmoset after amphetamine and haloperidol. Pharmacol Biochem Behav 14:345–351PubMedCrossRefGoogle Scholar
  54. Rolls ET (2000) The orbitofrontal cortex and reward. Cereb Cortex 10:284–294PubMedCrossRefGoogle Scholar
  55. 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 57:1518–1524PubMedCrossRefGoogle Scholar
  56. 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 19:1997–2002PubMedCrossRefGoogle Scholar
  57. Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593–1599PubMedCrossRefGoogle Scholar
  58. 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 28:1730–1740PubMedCrossRefGoogle Scholar
  59. Seiden LS, Sabol KE, Ricaurte GA (1993) Amphetamine: effects on catecholamine systems and behavior. Annu Rev Pharmacol Toxicol 33:639–676PubMedCrossRefGoogle Scholar
  60. 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 63:90–100PubMedCrossRefGoogle Scholar
  61. 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 30:1125–1134PubMedCrossRefGoogle Scholar
  62. 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 38:596–612PubMedCrossRefGoogle Scholar
  63. U.K.Department of Health (1999) Drug misuse and dependence—guidelines on clinical management. The Stationery Office, Norwich,UKGoogle Scholar
  64. United Nations Office on Drugs and Crime (2007) World drug report 2007. United Nations Office on Drugs and Crime (UNODC), New York, NY, USAGoogle Scholar
  65. 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 30:89–101PubMedCrossRefGoogle Scholar
  66. Verdejo-Garcia AJ, Perales JC, Perez-Garcia M (2007) Cognitive impulsivity in cocaine and heroin polysubstance abusers. Addict Behav 32:950–966PubMedCrossRefGoogle Scholar
  67. White FJ, Kalivas PW (1998) Neuroadaptations involved in amphetamine and cocaine addiction. Drug Alcohol Depend 51:141–153PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Karen D. Ersche
    • 1
    • 2
    Email author
  • Jonathan P. Roiser
    • 2
    • 3
    • 5
  • Trevor W. Robbins
    • 2
    • 4
  • Barbara J. Sahakian
    • 2
    • 3
  1. 1.Department of Psychiatry, Brain Mapping Unit, School of Clinical MedicineUniversity of CambridgeCambridgeUK
  2. 2.Behavioural and Clinical Neurosciences InstituteUniversity of CambridgeCambridgeUK
  3. 3.Department of Psychiatry, School of Clinical MedicineUniversity of CambridgeCambridgeUK
  4. 4.Department of Experimental PsychologyUniversity of CambridgeCambridgeUK
  5. 5.Institute of Cognitive NeuroscienceLondonUK

Personalised recommendations