PT  - JOURNAL ARTICLE
AU  - Karsten K. Madsen
AU  - Bjarke Ebert
AU  - Rasmus P. Clausen
AU  - Povl Krogsgaard-Larsen
AU  - Arne Schousboe
AU  - H. Steve White
TI  - Selective GABA Transporter Inhibitors Tiagabine and EF1502 Exhibit Mechanistic Differences in Their Ability to Modulate the Ataxia and Anticonvulsant Action of the Extrasynaptic GABA<sub>A</sub> Receptor Agonist Gaboxadol
AID  - 10.1124/jpet.111.179671
DP  - 2011 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 214--219
VI  - 338
IP  - 1
4099  - http://jpet.aspetjournals.org/content/338/1/214.short
4100  - http://jpet.aspetjournals.org/content/338/1/214.full
SO  - J Pharmacol Exp Ther2011 Jul 01; 338
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 [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] 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 N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502), 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 used 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, when administered 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 the anticonvulsant action of gaboxadol or reverse its Rotarod impairment. Taken together, these results highlight the mechanistic differences between tiagabine and EF1502 and support a functional role for BGT1 and extrasynaptic GABAA receptors.