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Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial

Abstract

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later, we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

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References

  1. Volkow ND, Morales M . The brain on drugs: from reward to addiction. Cell 2015; 162: 712–725.

    Article  CAS  Google Scholar 

  2. Kalivas PW, O’Brien C . Drug addiction as a pathology of staged neuroplasticity. Neuropsychopharmacology 2008; 33: 166–180.

    Article  CAS  Google Scholar 

  3. Goldstein RZ, Volkow ND . Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 2002; 159: 1642–1652.

    Article  Google Scholar 

  4. Dakwar E, Levin F, Foltin RW, Nunes EV, Hart CL . The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biol Psychiatry 2014; 76: 40–46.

    Article  CAS  Google Scholar 

  5. Popik P, Wrobel M, Rygla R, Bisaga A, Bespakov AY . Effect of memantine, an NMDA receptor antagonist, on place preference conditioned with drug and nondrug reinforces in mice. Behav Pharmacol 2003; 14: 237–244.

    Article  CAS  Google Scholar 

  6. Collins ED, Ward AS, McDowell DM, Foltin RW, Fischman MW . The effects of memantine on the subjective, reinforcing, and cardiovascular effects of cocaine in human. Behav Pharmacol 1998; 9: 587–598.

    Article  CAS  Google Scholar 

  7. Price KL, McRae-Clark AL, Saladin ME, Maria MM, DeSantis SM, Back SE et al. D-cycloserine and cocaine cue reactivity: preliminary findings. Am J Drug Alcohol Abuse 2009; 35: 434–438.

    Article  Google Scholar 

  8. Bisaga A, Aharonovich E, Cheng WY, Levin FR, Mariani JJ, Raby WN et al. A placebo-controlled trial of memantine for cocaine dependence with high-value voucher incentives during a pre-randomization lead-in period. Drug Alcohol Depend 2010; 111: 97–104.

    Article  CAS  Google Scholar 

  9. Berglind WJ, See RE, Fuchs RA, Ghee SM, Whitfield TW Jr, Miller SW et al. A BDNF infusion into the medial prefrontal cortex suppresses cocaine seeking in rats. Eur J Neurosci 2007; 26: 757.

    Article  Google Scholar 

  10. Hart CL, Haney M, Vosburg SK, Rubin E, Foltin RW . Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology 2008; 33: 761–768.

    Article  CAS  Google Scholar 

  11. Stoops WW, Rush CR . Agonist replacement for stimulant dependence: a review of clinical research. Curr Pharm Des 2013; 19: 7026–7035.

    Article  CAS  Google Scholar 

  12. Comer SD, Ashworth JB, Foltin RW, Johanson CE, Zacny JP, Walsh SL . The role of human drug self-administration procedures in the development of medications. Drug Alcohol Depend 2008; 96: 1–15.

    Article  CAS  Google Scholar 

  13. Iadarola ND, Niciu MJ, Richards EM, Vande Voort JL, Ballard ED, Lundin NB et al. Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review. Ther Adv Chronic Dis 2015; 6: 97–114.

    Article  CAS  Google Scholar 

  14. Haile CN, Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Foulkes A et al. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression. Int J Neuropsychopharmacol 2014; 17: 331–336.

    Article  CAS  Google Scholar 

  15. Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK et al. BDNF Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 2010; 71: 996–1005.

    Article  Google Scholar 

  16. Salvadore G, Cornwell BR, Colon-Rosario V, Coppola R, Grillon C, Zarate CA et al. Increased anterior cingulate cortical activity in response to fearful faces: a neurophysiological biomarker that predicts rapid antidepressant response to ketamine. Biol Psychiatry 2009; 65: 289–295.

    Article  CAS  Google Scholar 

  17. Scheidegger M, Walter M, Lehmann M, Metzger C, Grimm S, Boeker H et al. Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action. PloS One 2012; 7: e44799.

    Article  CAS  Google Scholar 

  18. First MB, Williams JBL, Spitzer RL, Gibbon M . Structured Clinical Interview for DSM-IV-TR Axis I Disorders Clinical Trials Version (SCID-CT). Biometrics Research, New York State Psychiatric Institute: New York, 2007.

    Google Scholar 

  19. William JB . A structured interview guide for the Hamilton Depression Scale. Arch Gen Psychiatry 1988; 45: 742–747.

    Article  Google Scholar 

  20. Bernstein EM, Putnam FW . Development, reliability, and validity of a dissociation scale. J Nerv Ment Dis 1986; 174: 727–735.

    Article  CAS  Google Scholar 

  21. Foltin RW, Fischman MW, Nestadt G, Stromberger H, Cornell EE, Pearlson GD . Demonstration of naturalistic methods for cocaine smoking by human volunteers. Drug Alcohol Depend 1990; 26: 145–154.

    Article  CAS  Google Scholar 

  22. Perry EB Jr, Cramer JA, Cho HS, Petrakis IL, Karper LP, Genovese A et al. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology 2007; 192: 253–260.

    Article  CAS  Google Scholar 

  23. Dakwar E, Anerella C, Hart CL, Levin FR, Mathew SJ, Nunes EV . Therapeutic infusions of ketamine: Do the psychoactive effects matter? Drug Alcohol Depend 2014; 136: 153–157.

    Article  CAS  Google Scholar 

  24. Stahl S . Stahl’s Essential Psvchopharmacoloav: Neuroscientific Basis and Clinical Applications. Cambridge University Press: New York, NY, USA, 2008.

    Google Scholar 

  25. Sklar GS, Zukin SR, Reilly TA . Adverse reactions to ketamine anesthesia: abolition by psychological technique. Anesthesia 1981; 36: 183–187.

    Article  CAS  Google Scholar 

  26. Bremner JJ, Krystal JH, Putnam FW, Southwick SM, Marmar C, Charney DS et al. Measurement of dissociative states with the Clinician Administered Dissociative States Scale (CADSS). J Trauma Stress 1998; 11: 125–136.

    Article  CAS  Google Scholar 

  27. SAS Inc. SAS. Cary, NC. 2003.

  28. Baer RA, Smith GT, Hopkins J, Krietemeyer J, Toney L . Using self-report assessment methods to explore facets of mindfulness. Assessment 2006; 13: 27–45.

    Article  Google Scholar 

  29. Tang YY, Posner MI, Rothbart MK, Volkow ND . Circuitry of self-control and its role in reducing addiction. Trends Cogn Sci (e-pub ahead of print 13 July 2015).

  30. Belujon P, Jakobowski NL, Dollish HK, Grace AA . Withdrawal from acute amphetamine induces an amygdala-driven attenuation of dopamine neuron activity: reversal by ketamine. Neuropsychopharmacology 2015; 41: 619–627.

    Article  Google Scholar 

  31. Sabino V, Narayan AR, Zeric T, Steardo L, Cottone P . mTOR activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats. Behav Brain Res 2013; 247: 9–16.

    Article  CAS  Google Scholar 

  32. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 20: 959–964.

    Article  Google Scholar 

  33. Krupitsky EM, Grinenko AY . Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs 1997; 29: 165–183.

    Article  CAS  Google Scholar 

  34. Ramo DE, Grov C, Delucchi K, Kelly BC, Parsons JT . Typology of club drug use among young adults recruited using time-space sampling. Drug Alcohol Depend 2010; 107: 119–127.

    Article  Google Scholar 

  35. Wan LB, Levitch CF, Perez AM, Brallier JW, Iosifescu DV, Chang LC et al. Ketamine safety and tolerability in clinical trials for treatment-resistant depression. J Clin Psychiatry 2015; 76: 247–252.

    Article  Google Scholar 

  36. Carter LP, Griffiths RR . Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend 2009; 105: S14–S25.

    Article  CAS  Google Scholar 

  37. Vollenweider FX, Kometer M . The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 2010; 11: 642–651.

    Article  CAS  Google Scholar 

  38. Niciu MJ, Henter ID, Luckenbaugh DA, Zarate CA Jr, Charney DS . Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds. Annu Rev Pharmacol Toxicol 2014; 54: 119–139.

    Article  CAS  Google Scholar 

  39. Larimer ME, Palmer RS, Marlatt GA . Relapse prevention. An overview of Marlatt's cognitive-behavioral model. Alcohol Res Health 1999; 23: 151–160.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank NIDA for funding this study through grants DA035472 and DA031771 awarded to Dr Dakwar. We also thank the New York State Psychiatric Institute for salary support and the provision of resources.

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Correspondence to E Dakwar.

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Dakwar, E., Hart, C., Levin, F. et al. Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial. Mol Psychiatry 22, 76–81 (2017). https://doi.org/10.1038/mp.2016.39

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