Pharmacological studies with a GABA uptake inhibitor in rats with kindled seizures in the amygdala.
The anticonvulsant effects of the inhibitor of the uptake of GABA, SKF 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), were investigated using the amygdala kindling seizure model in rats. The time course of activity of the racemic mixture, given orally, and the relative potencies of its d- and l-isomers, when given intraperitoneally, were tested. The drug SKF 89976-A was active, when given orally with anticonvulsant effects lasting 2-4 hr when given at 15 mg/kg, and 4-6 hr when given at 30 mg/kg. Peak inhibition of severity of seizures occurred at 1 hr after administration with an ED50 of 17.8 mg/kg. The d-isomer of SKF 89976-A was significantly more potent than the l-isomer and inhibited various parameters of kindled seizure activity in a dose-dependent manner. The l-isomer had significant effects on kindled seizures only at the largest dose (20 mg/kg). The ED50 of the d-isomer for inhibition of severity of seizures measured 0.5 hr after intraperitoneal injection, was 11.2 mg/kg and the antiseizure effects of the d-isomer lasted for 2-3 hr. Side effects of SKF 89976-A, such as sedation, abdominal muscle relaxation, rear limb splaying and ataxia, were seen at 30 mg/kg; there was a marked suppression of seizure activity with no side effects at smaller doses. The characterization of a biphasic kindled seizure allows for speculation regarding the role of GABAergic mechanisms in its pathogenesis and of the mechanism of action of SKF 89976-A.
Department of Pharmacology, New York State College of Veterinary Medicine, Cornell University, Ithaca 14853-6401.
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D000284:Administration, Oral; D000679:Amygdala / Q000187:drug effects*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004569:Electroencephalography; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects*; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000188:drug therapy*; D013237:Stereoisomerism; D013574:Synaptosomes / Q000378:metabolism
D000927:Anticonvulsants; D009557:Nipecotic Acids; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid