Effects of intranigral application of clinically-effective anticonvulsants on electroshock-induced seizures.
The authors sought to determine whether focal application of clinically-effective anticonvulsants to the substantia nigra produced anticonvulsant effects. To this end, the effects of phenobarbital, carbamazepine and phenytoin were examined on the electroshock seizure model in rats. Anticonvulsant efficacy was assessed by measuring the duration of tonic hindlimb extension before and after injection. It was found that application of phenobarbital into the nigra produced behavioral stereotypy and suppressed tonic hindlimb extension in a dose-dependent manner. These effects were spatially specific to the substantia nigra. By contrast, application of phenytoin or carbamazepine to the nigra produced neither anticonvulsant effects nor behavioral changes. Direct measurement of phenobarbital and carbamazepine in the substantia nigra showed that differences in concentration in the substantia nigra did not account for the lack of efficacy of carbamazepine. Moreover, concentrations of phenobarbital in the nigra after effective injection into the nigra exceeded concentrations in the nigra after effective systemic injections, by tenfold. Taken together, these data provide no compelling evidence that an action of the substantia nigra alone is sufficient to explain the therapeutic action of clinically-useful anticonvulsants.
Department of Pharmacology and Medicine (Neurology), Duke University Medical Center, Durham, North Carolina.
L S
LS
Chen
D S
DS
Millington
D A
DA
Maltby
J O
JO
McNamara
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002220:Carbamazepine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004597:Electroshock; D006614:Hindlimb / Q000503:physiopathology; D007267:Injections; D008297:Male; D010634:Phenobarbital / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D010672:Phenytoin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control*; D013378:Substantia Nigra / Q000378:metabolism
D000927:Anticonvulsants; D002220:Carbamazepine; D010672:Phenytoin; D010634:Phenobarbital