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.
- Received January 20, 2011.
- Revision received March 5, 2011.
- Accepted March 7, 2011.
- The American Society for Pharmacology and Experimental Therapeutics