Inhibition of the betaine-GABA transporter (mGAT2/BGT-1) modulates spontaneous electrographic bursting in the medial entorhinal cortex (mEC).
Disruptions in GABAergic neurotransmission have been implicated in numerous CNS disorders, including epilepsy and neuropathic pain. Selective inhibition of neuronal and glial GABA transporter subtypes may offer unique therapeutic options for regaining balance between inhibitory and excitatory systems. The ability of two GABA transport inhibitors to modulate inhibitory tone via inhibition of mGAT1 (tiagabine) or mGAT2/BGT-1 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-4-(methylamino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol), also known as EF1502) was evaluated using an in vitro model of spontaneous interictal-like bursting (SB). SBs were recorded extracellularly in combined mEC-HC horizontal brain slices (400 microm; 31+/-1 degrees C) obtained from KA-treated rats. Slice recordings demonstrated that EF1502 exhibited a concentration-dependent reduction in SB frequency. EF1502 significantly reduced SB rate to 32% of control at the 30 microM concentration, while reducing the area and duration of SB activity to 60% and 46% of control, respectively, at the 10 microM concentration. In contrast, the GAT1 selective inhibitor tiagabine (3, 10, and 30 microM) was unable to significantly reduce the frequency of SB activity in the mEC, despite significantly reducing both the duration (51% of control) and area (58% of control) of the SB at concentrations as low as 3 microM. The ability of EF1502, but not tiagabine, to inhibit SBs in the mEC suggests that this in vitro model of pharmacoresistant SB activity is useful to differentiate between novel anticonvulsants with similar mechanisms of action and suggests a therapeutic potential for non-GAT1 transport inhibitors.
Smith
Misty D
MD
Pharmacology & Toxicology, University of Utah Anticonvulsant Drug Development Program, Salt Lake City, UT, USA. Misty.Smith@utah.edu
Saunders
Gerald W
GW
Clausen
Rasmus P
RP
Frølund
Bente
B
Krogsgaard-Larsen
Povl
P
Larsson
Orla M
OM
Schousboe
Arne
A
Wilcox
Karen S
KS
White
H Steve
HS
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018728:Entorhinal Cortex / Q000187:drug effects / Q000503:physiopathology* / Q000528:radiation effects; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018755:GABA Agonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D007608:Kainic Acid; D008297:Male; D009557:Nipecotic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D000078308:Tiagabine
D002352:Carrier Proteins; C510806:EF1502; D018755:GABA Agonists; D050485:GABA Plasma Membrane Transport Proteins; D007555:Isoxazoles; D009557:Nipecotic Acids; C072207:betaine plasma membrane transport proteins; D007608:Kainic Acid; D000078308:Tiagabine