Paul W Czoty1, Robert W Gould2, Cormac A O'Donovan3, Michael A Nader2. 1. Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157-1083, United States of America. Electronic address: pczoty@wakehealth.edu. 2. Department of Physiology & Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC 27157-1083, United States of America. 3. Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC 27157-1083, United States of America.
Abstract
BACKGROUND: Drugs that increase inhibitory neuronal activity in the brain have been proposed as potential medications for stimulant use disorders. OBJECTIVE: The 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. METHODS: Three 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. RESULTS: Lower 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. CONCLUSION: These 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.
BACKGROUND: Drugs that increase inhibitory neuronal activity in the brain have been proposed as potential medications for stimulant use disorders. OBJECTIVE: The 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. METHODS: Three 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. RESULTS: Lower 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. CONCLUSION: These 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.
Authors: M Thorsten Doelken; Marc T Doelken; Thilo Hammen; Wolfgang Bogner; Angelika Mennecke; Andreas Stadlbauer; Uwe Boettcher; Arnd Doerfler; Hermann Stefan Journal: Epilepsia Date: 2010-08 Impact factor: 5.864
Authors: Mark H Pollack; J Eric Jensen; Naomi M Simon; Rebecca E Kaufman; Perry F Renshaw Journal: Prog Neuropsychopharmacol Biol Psychiatry Date: 2007-11-28 Impact factor: 5.067