Drug dependence study on vigabatrin in rhesus monkeys and rats.
The dependence potential of vigabatrin (gamma-vinyl GABA; R(-)/S(+)-4-amino-5-hexenoic acid, CAS 60643-86-9, MDL 71,754) was assessed in rhesus monkeys and rats. In the test of cross physical dependence potential, morphine- and barbital-dependent monkeys were both withdrawn from the respective drugs and the ability of vigabatrin to suppress the withdrawal signs was assessed. In morphine-dependent monkeys, subcutaneous doses of vigabatrin at 256 and 1000 mg/kg did not suppress withdrawal signs while subcutaneous doses of codeine phosphate at 4 and 8 mg/kg clearly suppressed the withdrawal signs. In barbital-dependent monkeys, subcutaneous and intravenous dose of vigabatrin, both at 1000 mg/kg, did not suppress the withdrawal signs, while intragastric doses of diazepam at 8 and 16 mg/kg clearly suppressed them. Thus, while the cross-physical dependence potential of codeine/morphine and of diazepam/barbital was clearly observable, vigabatrin appeared to have no such potential. In the test of physical dependence-producing potential with the drug-admixed food method in rats, vigabatrin and diazepam were given to rats mixed with food for 28 days in an increasing dosage schedule, followed by feeding a drug-free diet to observe withdrawal signs for 7 days. Upon withdrawal, no decrease in food intake or body weight was observed in the vigabatrin-treated groups, and the gross condition of the animals did not differ from that in the control group. In contrast, food intake and body weight decreased markedly in the diazepam group, and most rats showed hyperreactivity to external stimuli. Thus, while the physical dependence-producing potential of diazepam was clearly demonstrated, such potential was not shown with vigabatrin. In the test of reinforcing effect, 4 monkeys were allowed to self-administer pentobarbital at 1 mg/kg/infusion, or vigabatrin at 16, 32, and 64 mg/kg/infusion, intravenously through an indwelling catheter. Each drug was preceded and followed by saline self-administration for at least 7 days. Active self-administration of pentobarbital was observed in all monkeys tested, while the self-administration rate of vigabatrin did not differ from saline. Thus, while the reinforcing effect of pentobarbital was clearly observed, such effect was not observable with vigabatrin. Based on these results, it was considered that vigabatrin was devoid of dependence potential.
Takada
K
K
Preclinical Research Laboratories, Inc., Kawasaki, Japan.
Yanagita
T
T
D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001462:Barbital / Q000009:adverse effects; D003216:Conditioning, Operant; D005260:Female; D006993:Hypnotics and Sedatives / Q000009:adverse effects; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000523:psychology*; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology
D000701:Analgesics, Opioid; D000927:Anticonvulsants; D006993:Hypnotics and Sedatives; D005680:gamma-Aminobutyric Acid; D001462:Barbital; D009020:Morphine; D020888:Vigabatrin