RT Journal Article
SR Electronic
T1 The selective GAT inhibitors tiagabine and N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502) exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA<sub>A</sub> receptor agonist gaboxadol.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.111.179671
DO 10.1124/jpet.111.179671
A1 Karsten K. Madsen
A1 Bjarke Ebert
A1 Rasmus P, Clausen
A1 Povl Krogsgaard-Larsen
A1 Arne Schousboe
A1 H. Steve White
YR 2011
UL http://jpet.aspetjournals.org/content/early/2011/03/30/jpet.111.179671.abstract
AB Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine (Gabitril®) [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid] has proven to be an effective treatment strategy for focal seizures. Even though less is known about the therapeutic potential of other GABA transport inhibitors, previous investigations have demonstrated that EF1502 [N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol], which like tiagabine is inactive on GABAA receptors, inhibits both GAT1 and the extrasynaptic GABA and betaine transporter BGT1 and exerts a synergistic anticonvulsant effect when tested in combination with tiagabine. In the present study, the anticonvulsant activity and motor impairment associated with systemic administration of gaboxadol [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol], which, at the doses employed in this study (i.e., 1-5 mg/kg) selectively activates extrasynaptic α4 containing GABAA receptors, was determined alone and in combination with either tiagabine or EF1502 using Frings audiogenic seizure-susceptible and CF1 mice. EF1502, in combination with gaboxadol resulted in reduced anticonvulsant efficacy and rotarod impairment associated with gaboxadol. In contrast, tiagabine, when administered in combination with gaboxadol did not modify gaboxadol's anticonvulsant action or reverse its rotarod impairment. Collectively, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABAA receptors.