Increase in drug-induced seizure susceptibility of transgenic mice overexpressing GABA transporter-1.
OBJECTIVE
The changes of seizure susceptibility of transgenic mice overexpressing GABA transporter-1 (GAT-1) were studied to clarify the possible role of GABAergic transmission in epileptogenesis.


METHODS
Seizures were induced by intraperitoneal administration of pentylenetetrazol (PTZ), picrotoxin (PIC), or kainic acid (KA) respectively. The anticonvulsant effect of ethyl nipecotate was tested by its intraperitoneal injection 15 min before the administration of the epileptogenic agents.


RESULTS
The percentages of occurrence of clonic seizures induced by PTZ 45 mg/kg, PIC 2.5 mg/kg, or KA 20 mg/kg in GAT-1 transgenic mice were 88.9 %, 100 %, and 83.3 % respectively, whereas those in control C57BL/6J mice were 42.9 %, 57.1 %, and 33.3 %. The percentages of occurrence of tonic seizures induced by PTZ 45 mg/kg, PIC 2.5 mg/kg, or KA 20 mg/kg in transgenic mice were 88.9 %, 100 %, and 83.3 % respectively, and whereas those in control mice were 28.6 %, 42.9 %, and 16.7 %. The latencies of both clonic and tonic seizures onset in transgenic mice were markedly shortened compared with those in control animals. The results indicated that GAT-1 transgenic mice showed increased susceptibility to seizures induced by the anti-GABAergic convulsive drugs (PTZ, PIC), as well as glutamic receptor agonist (KA). Ethyl nipecotate, inhibitor of GAT-1, inhibited PTZ-induced seizures in both GAT-1 transgenic and C57BL/6J mice. The incidence of seizures was decreased after the application of ethyl nipecotate, and the latencies to the onset of clonic or tonic seizures were also prolonged.


CONCLUSIONS
The increase in seizure susceptibility of transgenic mice over-expressing GAT-1 is an evidence for involvement of GABAergic transmission in epileptogenesis, and this transgenic mouse might be a useful animal model for study on the role of GABAergic transmission in epileptogenesis.
Zhao
Wen-Juan
WJ
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Ma
Ying-Hua
YH
Fei
Jian
J
Mei
Zhen-Tong
ZT
Guo
Li-He
LH
D000818:Animals; D030801:Animals, Genetically Modified; D000927:Anticonvulsants / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins; D020022:Genetic Predisposition to Disease; D007608:Kainic Acid; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009557:Nipecotic Acids / Q000494:pharmacology*; D010433:Pentylenetetrazole; D010852:Picrotoxin; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*
D000927:Anticonvulsants; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D007608:Kainic Acid; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D010433:Pentylenetetrazole; D010852:Picrotoxin; C493414:Slc6a1 protein, mouse; C038002:nipecotic acid ethyl ester