title: Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol.
abstract: 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 GABA(A) 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 GABA(A) 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 GABA(A) receptors.
authors: Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark. swhite@hsc.utah.edu
authors: Karsten K
authors: KK
authors: Madsen
authors: Bjarke
authors: B
authors: Ebert
authors: Rasmus P
authors: RP
authors: Clausen
authors: Povl
authors: P
authors: Krogsgaard-Larsen
authors: Arne
authors: A
authors: Schousboe
authors: H Steve
authors: HS
authors: White
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001259:Ataxia / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology*; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009557:Nipecotic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000502:physiology; D013569:Synapses / Q000187:drug effects; D000078308:Tiagabine
chemical_list: D000927:Anticonvulsants; C510806:EF1502; D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D007555:Isoxazoles; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; C490439:Slc6a12 protein, mouse; C015542:gaboxadol; D000078308:Tiagabine