Advertisement

Psychopharmacology

, Volume 236, Issue 7, pp 2143–2153 | Cite as

Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates

  • Brian D. KangasEmail author
  • Rachel J. Doyle
  • Stephen J. Kohut
  • Jack Bergman
  • Marc J. Kaufman
Original Investigation
  • 209 Downloads

Abstract

Rationale

Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine’s deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., N-acetylcysteine [NAC]) may attenuate CUD-related relapse behavior.

Objectives

The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior.

Methods

First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13–3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement.

Results

Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups.

Conclusions

The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

Keywords

Self-administration Cocaine N-acetylcysteine Learning Cognitive flexibility Reinstatement Nonhuman Primates 

Notes

Acknowledgments

The authors thank Roger Spealman for comments on a previous version of this manuscript.

Funding information

This research was supported by grants K01-DA035974 (BDK) and R21-DA039301 (MJK) from the National Institute on Drug Abuse.

Compliance with ethical standards

The protocol for the present studies was approved by the Institutional Animal Care and Use Committee at McLean Hospital in a facility licensed by the US Department of Agriculture and in accordance with guidelines provided by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animals Resources, Commission on Life Sciences (National Research Council 2011).

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. Aharonovich E, Nunes E, Hasin D (2003) Cognitive impairment, retention and abstinence among cocaine abusers in cognitive-behavioral treatment. Drug Alcohol Depend 71:207–211CrossRefPubMedPubMedCentralGoogle Scholar
  2. Aharonovich E, Hasin DS, Brooks AC, Liu X, Bisaga A, Nunes EV (2006) Cognitive deficits predict low treatment retention in cocaine dependent patients. Drug Alcohol Depend 81:313–322CrossRefPubMedGoogle Scholar
  3. Amen SL, Piacentine LB, Ahmad ME, Li SJ, Mantsch JR, Risinger RC, Baker DA (2011) Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology 36:871–878CrossRefPubMedGoogle Scholar
  4. Baker DA, McFarland K, Lake RW, Shen H, Tang XC, Toda S, Kalivas PW (2003) Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6:743–749CrossRefPubMedGoogle Scholar
  5. Bauzo RM, Kimmel HL, Howell LL (2012) The cystine-glutamate transporter enhancer N-acetyl-L-cysteine attenuates cocaine-induced changes in striatal dopamine but not self-administration in squirrel monkeys. Pharmacol Biochem Behav 101:288–296CrossRefPubMedGoogle Scholar
  6. Ben-Shahar OM, Szumlinski KK, Lominac KD, Cohen A, Gordon E, Ploense KL, DeMartini J, Bernstein N, Rudy NM, Nabhan AN, Sacramento A, Pagano K, Carosso GA, Woodward N (2012) Extended access to cocaine self-administration results in reduced glutamate function within the medial prefrontal cortex. Addict Biol 17:746–757CrossRefPubMedPubMedCentralGoogle Scholar
  7. Berk M, Malhi GS, Gray LJ, Dean OM (2013) The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci 34:167–177CrossRefPubMedGoogle Scholar
  8. Charntikov S, Pittenger ST, Pudiak CM, Bevins RA (2018) The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamine-triggered reinstatement of female rats. Neuropharmacology 135:487–495CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chudasama Y (2011) Animal models of prefrontal-executive function. Behav Neurosci 125:327–343CrossRefPubMedGoogle Scholar
  10. Easton A (2005) Behavioural flexibility, social learning, and the frontal cortex. In: Easton A, Emery NJ (eds) The cognitive neuroscience of social behavior. Psychology Press, New York, pp 59–80CrossRefGoogle Scholar
  11. Frankowska M, Jastrzębska J, Nowak E, Białko M, Przegaliński E, Filip M (2014) The effects of N-acetylcysteine on cocaine reward and seeking behaviors in a rat model of depression. Behav Brain Res 266:108–118CrossRefPubMedGoogle Scholar
  12. Gould RW, Gage HD, Nader MA (2012) Effects of chronic cocaine self-administration on cognition and cerebral glucose utilization in rhesus monkeys. Biol Psychiatry 72:856–863CrossRefPubMedPubMedCentralGoogle Scholar
  13. Grandjean EM, Berthet P, Ruffmann R, Leuenberger P (2000) Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebocontrolled clinical trials. Clin Ther 22:209–221CrossRefPubMedGoogle Scholar
  14. Groman SM, Lee B, Seu E, James AS, Feiler K, Mandelkern MA, London ED, Jentsch JD (2012) Dysregulation of D2-mediated dopamine transmission in monkeys after chronic escalating methamphetamine exposure. J Neurosci 32:5843–5852CrossRefPubMedPubMedCentralGoogle Scholar
  15. Groman SM, Morales AM, Lee B, London ED, Jentsch JD (2013) Methamphetamine-induced increases in putamen gray matter associate with inhibitory control. Psychopharmacology 229:527–538CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hagos FT, Daood MJ, Ocque JA, Nolin TD, Bayir H, Poloyac SM, Kochanek PM, Clark RS, Empey PE (2017) Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine. Xenobiotica 47:346–353PubMedGoogle Scholar
  17. Hakami AY, Sari Y (2017) β-Lactamase inhibitor, clavulanic acid, attenuates ethanol intake and increases glial glutamate transporters expression in alcohol preferring rats. Neurosci Lett 657:140–145CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hakami AY, Alshehri FS, Sari Y (2018) β-lactams modulate astroglial glutamate transporters and attenuate dependence to CP 55,940, a CB1 receptor agonist, in rat model. Behav Brain Res S0166-4328(18):30743–30745Google Scholar
  19. Herd JA, Morse WH, Kelleher RT, Jones LG (1969) Arterial hypertension in the squirrel monkey during behavioral experiments. Am J Phys 217:24–29CrossRefGoogle Scholar
  20. Hodebourg R, Murray JE, Fouyssac M, Puaud M, Everitt BJ, Belin D (2018) Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine. Eur J Neurosci.  https://doi.org/10.1111/ejn.13894
  21. Izquierdo A, Jentsch JD (2012) Reversal learning as a measure of impulsive and compulsive behavior in addictions. Psychopharmacology 219:607–620CrossRefPubMedGoogle Scholar
  22. Jastrzębska J, Frankowska M, Filip M, Atlas D (2016) N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement. Psychopharmacology 233:3437–3448CrossRefPubMedGoogle Scholar
  23. Jentsch JD, Olausson P, De La Garza R 2nd, Taylor JR (2002) Impairments of reversal learning and response perseveration after repeated, intermittent cocaine administrations to monkeys. Neuropsychopharmacology 26:183–190CrossRefPubMedGoogle Scholar
  24. Johnson BA, Ait-Daoud N, Wang XQ, Penberthy JK, Javors MA, Seneviratne C, Liu L (2013) Topiramate for the treatment of cocaine addiction: a randomized clinical trial. JAMA Psychiatry 70:1338–1346CrossRefPubMedGoogle Scholar
  25. Kalivas PW, Volkow ND (2011) New medications for drug addiction hiding in glutamatergic neuroplasticity. Mol Psychiatry 16:974–986CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kangas BD, Bergman J (2012) A novel touch-sensitive apparatus for behavioral studies in unrestrained squirrel monkeys. J Neurosci Methods 209:331–336CrossRefPubMedPubMedCentralGoogle Scholar
  27. Kangas BD, Bergman J (2014) Repeated acquisition and discrimination reversal in the squirrel monkey (Saimiri sciureus). Anim Cogn 17:221–228CrossRefPubMedGoogle Scholar
  28. Kangas BD, Bergman J (2016) Effects of self-administered methamphetamine on discrimination learning and reversal in nonhuman primates. Psychopharmacology 233:373–380CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kangas BD, Bergman J (2017) Touchscreen technology in the study of cognition-related behavior. Behav Pharmacol 28:623–629CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kangas BD, Leonard MZ, Shukla VG, Alapafuja SO, Nikas SP, Makriyannis A, Bergman J (2016) Comparisons of Δ9-tetrahydrocannabinol and anandamide on a battery of cognition-related behavior in nonhuman primates. J Pharmacol Exp Ther 357:125–133CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kau KS, Madayag A, Mantsch JR, Grier MD, Abdulhameed O, Baker DA (2008) Blunted cysteine-glutamate antiporter function in the nucleus accumbens promotes cocaine induced drug seeking. Neuroscience 155:530–537CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kelleher RT, Morse WH (1968) Determinants of the specificity of behavioral effects of drugs. Ergeb Physiol Biol Chem Exp Pharmakol 60:1–56Google Scholar
  33. Kim J, John J, Langford D, Walker E, Ward S, Rawls SM (2016) Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice. Amino Acids 48:689–696CrossRefPubMedGoogle Scholar
  34. Knackstedt LA, Melendez RI, Kalivas PW (2010) Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biol Psychiatry 67:81–84CrossRefPubMedPubMedCentralGoogle Scholar
  35. Knackstedt LA, Trantham-Davidson HL, Schwendt M (2014) The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning. Addict Biol 19:87–101CrossRefPubMedGoogle Scholar
  36. Kuhar MJ, Ritz MC, Boja JW (1991) The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 14:299–302CrossRefPubMedGoogle Scholar
  37. Kupchik YM, Moussawi K, Tang XC, Wang X, Kalivas BC, Kolokithas R, Ogburn KB, Kalivas PW (2012) The effect of N-acetylcysteine in the nucleus accumbens on neurotransmission and relapse to cocaine. Biol Psychiatry 71:978–986CrossRefPubMedGoogle Scholar
  38. LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, Brady K, Kalivas PW, Malcolm R (2007) Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry 164:1115–1117CrossRefPubMedGoogle Scholar
  39. LaRowe SD, Kalivas PW, Nicholas JS, Randall PK, Mardikian PN, Malcolm RJ (2013) A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am J Addict 22:443–452CrossRefPubMedPubMedCentralGoogle Scholar
  40. Levi Bolin B, Alcorn JL 3rd, Lile JA, Rush CR, Rayapati AO, Hays LR, Stoops WW (2017) N-acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order. Drug Alcohol Depend 178:452–460CrossRefPubMedPubMedCentralGoogle Scholar
  41. Liu S, Heitz RP, Sampson AR, Zhang W, Bradberry CW (2008) Evidence of temporal cortical dysfunction in rhesus monkeys following chronic cocaine self-administration. Cereb Cortex 18:2109–2116CrossRefPubMedGoogle Scholar
  42. Liu X, Jensen JE, Gillis TE, Zuo CS, Prescot AP, Brimson M, Cayetano K, Renshaw PF, Kaufman MJ (2011) Chronic cocaine exposure induces putamen glutamate and glutamine metabolite abnormalities in squirrel monkeys. Psychopharmacology 217:367–375CrossRefPubMedPubMedCentralGoogle Scholar
  43. Mackintosh NJ, McGonigle B, Holgate V, Vanderver V (1968) Factors underlying improvement in serial reversal learning. Can J Psychol 22:85–95CrossRefPubMedGoogle Scholar
  44. Mardikian PN, LaRowe SD, Hedden S, Kalivas PW, Malcolm RJ (2007) An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog Neuro-Psychopharmacol Biol Psychiatry 31:389–394CrossRefGoogle Scholar
  45. Martinez D, Slifstein M, Nabulsi N, Grassetti A, Urban NB, Perez A, Liu F, Lin SF, Ropchan J, Mao X, Kegeles LS, Shungu DC, Carson RE, Huang Y (2014) Imaging glutamate homeostasis in cocaine addiction with the metabotropic glutamate receptor 5 positron emission tomography radiotracer [11C]ABP688 and magnetic resonance spectroscopy. Biol Psychiatry 75:165–171CrossRefPubMedGoogle Scholar
  46. McClure EA, Gipson CD, Malcolm RJ, Kalivas PW, Gray KM (2014) Potential role of N-acetylcysteine in the management of substance use disorders. CNS Drugs 28:95–106CrossRefPubMedPubMedCentralGoogle Scholar
  47. Moeller FG, Dougherty DM, Barratt ES, Schmitz JM, Swann AC, Grabowski J (2001) The impact of impulsivity on cocaine use and retention in treatment. J Subst Abus Treat 21:193–198CrossRefGoogle Scholar
  48. Moran MM, McFarland K, Melendez RI, Kalivas PW, Seamans JK (2005) Cystine/glutamate exchange regulatesmetabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. J Neurosci 25:6389–6393CrossRefPubMedPubMedCentralGoogle Scholar
  49. Moussawi K, Zhou W, Shen H, Reichel CM, See RE, Carr DB, Kalivas PW (2011) Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse. Proc Natl Acad Sci U S A 108:385–390CrossRefPubMedGoogle Scholar
  50. National Institute on Drug Abuse (NIDA); National Institutes of Health; U.S. Department of Health and Human Services. Cocaine: Drug Facts, July 2018. www.drugabuse.gov/publications/drugfacts/cocaine; accessed 18 Nov 2018
  51. National Research Council (2011) Guide for the care and use of laboratory animals: eighth edition. National Academy Press, Washington DCGoogle Scholar
  52. Porter JN, Olsen AS, Gurnsey K, Dugan BP, Jedema HP, Bradberry CW (2011) Chronic cocaine self-administration in rhesus monkeys: impact on associative learning, cognitive control, and working memory. J Neurosci 31:4926–4934CrossRefPubMedPubMedCentralGoogle Scholar
  53. Porter JN, Gurnsey K, Jedema HP, Bradberry CW (2013) Latent vulnerability in cognitive performance following chronic cocaine self-administration in rhesus monkeys. Psychopharmacology 226:139–146CrossRefPubMedGoogle Scholar
  54. Potvin S, Stavro K, Rizkallah E, Pelletier J (2014) Cocaine and cognition: a systematic quantitative review. J Addict Med 8:368–376CrossRefPubMedGoogle Scholar
  55. Quintanilla ME, Morales P, Ezquer F, Ezquer M, Herrera-Marschitz M, Israel Y (2018) Commonality of ethanol and nicotine reinforcement and relapse in Wistar-derived UChB rats: inhibition by N-acetylcysteine. Alcohol Clin Exp Res 42:1988–1999CrossRefPubMedGoogle Scholar
  56. Ramirez-Niño AM, D'Souza MS, Markou A (2013) N-acetylcysteine decreased nicotine self-administration and cue-induced reinstatement of nicotine seeking in rats: comparison with the effects of N-acetylcysteine on food responding and food seeking. Psychopharmacology 225:473–482CrossRefPubMedGoogle Scholar
  57. Reichel CM, Moussawi K, Do PH, Kalivas PW, See RE (2011) Chronic N-acetylcysteine during abstinence or extinction after cocaine self-administration produces enduring reductions in drug seeking. J Pharmacol Exp Ther 337:487–493CrossRefPubMedPubMedCentralGoogle Scholar
  58. Reissner KJ, Gipson CD, Tran PK, Knackstedt LA, Scofield MD, Kalivas PW (2015) Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement. Addict Biol 20:316–323CrossRefPubMedGoogle Scholar
  59. Repine JE, Bast A, Lankhorst I (1997) Oxidative stress in chronic obstructive pulmonary disease. Oxidative Stress Study Group. Am J Resp Crit Care Med 156:341–357CrossRefPubMedGoogle Scholar
  60. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223CrossRefPubMedGoogle Scholar
  61. Samuni Y, Goldstein S, Dean OM, Berk M (2013) The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta 1830:4117–4129CrossRefPubMedGoogle Scholar
  62. Schmaal L, Veltman DJ, Nederveen A, van den Brink W, Goudriaan AE (2012) N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology 37:2143–2152CrossRefPubMedPubMedCentralGoogle Scholar
  63. Skvarc DR, Dean OM, Byrne LK, Gray L, Lane S, Lewis M, Fernandes BS, Berk M, Marriott A (2017) The effect of N-acetylcysteine (NAC) on human cognition—a systematic review. Neurosci Biobehav Rev 78:44–56CrossRefPubMedGoogle Scholar
  64. Spronk DB, van Wel JH, Ramaekers JG, Verkes RJ (2013) Characterizing the cognitive effects of cocaine: a comprehensive review. Neurosci Biobehav Rev 37:1838–1859CrossRefPubMedGoogle Scholar
  65. Turner TH, LaRowe S, Horner MD, Herron J, Malcolm R (2009) Measures of cognitive functioning as predictors of treatment outcome for cocaine dependence. J Subst Abus Treat 37:328–334CrossRefGoogle Scholar
  66. Verdejo-García A, Betanzos-Espinosa P, Lozano OM, Vergara-Moragues E, González-Saiz F, Fernández-Calderón F, Bilbao-Acedos I, Pérez-García M (2012) Self-regulation and treatment retention in cocaine dependent individuals: a longitudinal study. Drug Alcohol Depend 122:142–148CrossRefPubMedGoogle Scholar
  67. Winhusen T, Lewis D, Adinoff B, Brigham G, Kropp F, Donovan DM, Seamans CL, Hodgkins CC, Dicenzo JC, Botero CL, Jones DR, Somoza E (2013a) Impulsivity is associated with treatment non-completion in cocaine- and methamphetamine-dependent patients but differs in nature as a function of stimulant-dependence diagnosis. J Subst Abus Treat 44:541–547CrossRefGoogle Scholar
  68. Winhusen TM, Somoza EC, Lewis DF, Kropp FB, Horigian VE, Adinoff B (2013b) Frontal systems deficits in stimulant-dependent patients: evidence of pre-illness dysfunction and relationship to treatment response. Drug Alcohol Depend 127:94–100CrossRefPubMedGoogle Scholar
  69. Wood S, Sage JR, Shuman T, Anagnostaras SG (2013) Psychostimulants and cognition: a continuum of behavioral and cognitive activation. Pharmacol Rev 66:193–221CrossRefPubMedGoogle Scholar
  70. Woolverton WL, Schuster CR (1978) Behavioral tolerance to cocaine. NIDA Res Monogr 18:127–141Google Scholar
  71. Yang S, Salmeron BJ, Ross TJ, Xi ZX, Stein EA, Yang Y (2009) Lower glutamate levels in rostral anterior cingulate of chronic cocaine users—A (1)H-MRS study using TE-averaged PRESS at 3 T with an optimized quantification strategy. Psychiatry Res 174:171–176CrossRefPubMedPubMedCentralGoogle Scholar
  72. Zhou W, Kalivas PW (2008) N-acetylcysteine reduces extinction responding and induces enduring reductions in cue- and heroin-induced drug-seeking. Biol Psychiatry 63:338–340CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Harvard Medical SchoolMcLean HospitalBelmontUSA

Personalised recommendations