Effects of ketamine treatment on cocaine-induced reinstatement and disruption of functional connectivity in unanesthetized rhesus monkeys
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Substance use disorders are characterized by a loss of executive control over reward-based decision-making, and disruption of fronto-striatal connectivity has been implicated in this process. Sub-anesthetic ketamine has recently been shown to bolster fronto-striatal connectivity in drug-naïve subjects.
The influence of ketamine treatment was examined on the disruptive effects of cocaine on functional connectivity (FC) and on cocaine-seeking behavior in female rhesus monkeys.
Three female rhesus were trained for unanesthetized MRI scanning. Each received three drug-naïve/abstinent pharmacological MRI scans with acute injections of saline, cocaine (0.3 mg/kg i.v.), and cocaine (0.3 mg/kg i.v.) 48-h after a ketamine treatment (low dose = 0.345 mg/kg bolus + 0.256 mg/kg/h for 1 h; i.v.), and a fourth scan with saline injection following 2 months of daily cocaine self-administration. A separate cohort of five rhesus (4 female), all with extensive histories of cocaine exposure, underwent reinstatement testing 48 h after ketamine (or vehicle) treatment. Two sub-anesthetic doses were tested: low dose and high dose = 0.69 mg/kg + 0.512 mg/kg/h for 1 h.
Ketamine treatment attenuated the effects of cocaine on both global and fronto-striatal FC in drug-naïve/abstinent subjects. Two months of daily cocaine self-administration led to prolonged disruption of both global and fronto-striatal FC. Cocaine-seeking behavior during reinstatement was reduced following ketamine treatment at the low dose, but not high dose.
These findings illustrate the disruptive effects of cocaine on functional connectivity and provide evidence for the potential efficacy of ketamine as a treatment for stimulant use disorder.
KeywordsKetamine Cocaine Functional connectivity Pharmacological MRI Self-administration Nonhuman primates Reinstatement Addiction
Special thanks to Dr. Lais Berro and Dr. Maylen Perez-Diaz for behavioral methods training; to Juliet Brown for performing the catheter surgeries; and to technicians Marisa Olsen, Erin Siebert, Ruth Connelly, and Sudeep Patel for laboratory and imaging support.
This research was supported by P51OD11132 (Yerkes National Primate Research Center) and DA031246 (LLH).
Compliance with ethical standards
All protocols and animal care and handling strictly followed the National Institutes of Health Guide for the Care and Use of Laboratory Animals (8th edition, revised 2011) and the recommendations of the American Association for Accreditation of Laboratory Animal Care and were approved by the Institutional Animal Care and Use Committee of Emory University.
Conflict of interest
The authors declare that they have no conflict of interest.
- Berro LF, Perez Diaz M, Maltbie E, Howell LL (2017) Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys. Psychopharmacology (Berl)Google Scholar
- Camchong J, Macdonald AW 3rd, Mueller BA, Nelson B, Specker S, Slaymaker V, Lim KO (2014) Changes in resting functional connectivity during abstinence in stimulant use disorder: a preliminary comparison of relapsers and abstainers. Drug Alcohol Depend 139:145–151CrossRefPubMedPubMedCentralGoogle Scholar
- Contreras-Rodriguez O, Albein-Urios N, Perales JC, Martinez-Gonzalez JM, Vilar-Lopez R, Fernandez-Serrano MJ, Lozano-Rojas O, Verdejo-Garcia A (2015) Cocaine-specific neuroplasticity in the ventral striatum network is linked to delay discounting and drug relapse. Addiction 110:1953–1962CrossRefPubMedGoogle Scholar
- Dakwar E, Hart CL, Levin FR, Nunes EV, Foltin RW (2016) Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial. Mol PsychiatryGoogle Scholar
- Howell LL, Fantegrossi WE (2009) Intravenous drug self-administration in nonhuman primates. In: Buccafusco JJ (ed) Methods of Behavior Analysis in Neuroscience (Frontiers in Neuroscience), Boca Raton (FL)Google Scholar
- London ED, Cascella NG, Wong DF, Phillips RL, Dannals RF, Links JM, Herning R, Grayson R, Jaffe JH, Wagner HN Jr (1990) Cocaine-induced reduction of glucose utilization in human brain. A study using positron emission tomography and [fluorine 18]-fluorodeoxyglucose. Arch Gen Psychiatry 47:567–574CrossRefPubMedGoogle Scholar
- National Research Council (U.S.). Committee for the Update of the Guide for the Care and Use of Laboratory Animals., Institute for Laboratory Animal Research (U.S.), National Academies Press (U.S.) (2011) Guide for the care and use of laboratory animals. National Academies Press, Washington, D.C., p xxv, 220 pGoogle Scholar
- Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28:631–637CrossRefPubMedGoogle Scholar
- RStudio T (2016) RStudio: integrated development environment for R. RStudio, Inc., Boston, MAGoogle Scholar
- Sanacora G, Frye MA, McDonald W, Mathew SJ, Turner MS, Schatzberg AF, Summergrad P, Nemeroff CB, American Psychiatric Association Council of Research Task Force on Novel B, Treatments (2017) A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry 74:399–405CrossRefPubMedGoogle Scholar
- Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, Bannister PR, De Luca M, Drobnjak I, Flitney DE, Niazy RK, Saunders J, Vickers J, Zhang Y, De Stefano N, Brady JM, Matthews PM (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23(Suppl 1):S208–S219CrossRefPubMedGoogle Scholar
- Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481–486CrossRefPubMedPubMedCentralGoogle Scholar