Chronic levetiracetam (Keppra®) treatment increases the reinforcing strength of cocaine in rhesus monkeys

Abstract

BackgroundDrugs that increase inhibitory neuronal activity in the brain have been proposed as potential medications for stimulant use disorders. ObjectiveThe present study assessed the ability of chronically administered levetiracetam (Keppra®), a clinically available anticonvulsant drug that increases GABA by binding to synaptic vesicle glycoprotein 2A, to modulate the reinforcing strength of cocaine in monkeys. MethodsThree adult male rhesus monkeys (Macaca mulatta) self-administered cocaine intravenously each day under a progressive-ratio (PR) schedule of reinforcement. Two monkeys also responded to receive food pellets under a 50-response fixed-ratio schedule (FR 50) each morning. After determining a cocaine dose-response curve (0.001–0.3 mg/kg per injection, i.v.) in the evening, levetiracetam (5–75 mg/kg, p.o., b.i.d.) was administered for 12–16 days per dose. To model a treatment setting, cocaine self-administration sessions were conducted using the PR schedule every 4 days during levetiracetam treatment. After tapering the dose of levetiracetam over two weeks in the absence of cocaine sessions, cocaine dose-effect curves were re-determined. ResultsLower doses of levetiracetam produced non-systematic fluctuations in numbers of cocaine injections received in each subject, whereas the highest tested dose significantly increased the reinforcing strength of cocaine; no effects on food-maintained responding were observed. After termination of levetiracetam treatment, dose-effect curves for cocaine self-administration were shifted to the left in two monkeys. ConclusionThese data suggest that levetiracetam is not likely to be an efficacious pharmacotherapy for cocaine dependence. Rather, sensitivity to cocaine may be increased during and after levetiracetam treatment.