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.
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