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Effects of ketamine treatment on cocaine-induced reinstatement and disruption of functional connectivity in unanesthetized rhesus monkeys

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Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusion

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.

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Acknowledgements

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.

Funding

This research was supported by P51OD11132 (Yerkes National Primate Research Center) and DA031246 (LLH).

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Authors and Affiliations

  1. Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd NE, Atlanta, GA, 30329, USA

    Eric A. Maltbie, Kaundinya S. Gopinath & Leonard L. Howell

  2. Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, 30329, USA

    Kaundinya S. Gopinath

  3. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, 30329, USA

    Leonard L. Howell

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  1. Eric A. Maltbie
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  2. Kaundinya S. Gopinath
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  3. Leonard L. Howell
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Correspondence to Leonard L. Howell.

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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.

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Maltbie, E.A., Gopinath, K.S. & Howell, L.L. Effects of ketamine treatment on cocaine-induced reinstatement and disruption of functional connectivity in unanesthetized rhesus monkeys. Psychopharmacology 236, 2105–2118 (2019). https://doi.org/10.1007/s00213-019-05204-4

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