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

• Published in: Psychopharmacology Vol. 236; no. 7; pp. 2105 - 2118
• Main Authors: Maltbie, Eric A., Gopinath, Kaundinya S., Howell, Leonard L.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2019; Springer; Springer Nature B.V
• Subjects: Anesthetics, Dissociative - pharmacology; Anesthetics, Dissociative - therapeutic use; Animal behavior; Animals; Biomedical and Life Sciences; Biomedicine; Central nervous system agents; Cocaine; Cocaine - administration & dosage; Cocaine-Related Disorders - diagnostic imaging; Cocaine-Related Disorders - drug therapy; Corpus Striatum - diagnostic imaging; Corpus Striatum - drug effects; Decision making; Disruption; Drug dosages; Drug self-administration; Executive function; Extinction, Psychological - drug effects; Female; Frontal Lobe - diagnostic imaging; Frontal Lobe - drug effects; Ketamine; Ketamine - pharmacology; Ketamine - therapeutic use; Macaca mulatta; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Monkeys; Neostriatum; Nerve Net - diagnostic imaging; Nerve Net - drug effects; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Reinforcement; Reinstatement; Reward; Self Administration; Substance use; Treatment Outcome; Functional connectivity; Pharmacological MRI; Self-administration; Ketamine; Addiction; Reinstatement; Nonhuman primates; Cocaine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-019-05204-4

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.