GABA transporters as drug targets for modulation of GABAergic activity.

The identification and subsequent development of the GABA transport inhibitor tiagabine has confirmed the important role that GABA transporters play in the control of CNS excitability. Tiagabine was later demonstrated to be a selective inhibitor of the GABA transporter GAT1. Although selective for GAT1, tiagabine lacks cell type selectivity and is an equipotent inhibitor of neuronal and glial GAT1. To date, four GABA transporters have been cloned, i.e., GAT1-4. The finding that some of these display differential cellular and regional expression patterns suggests that drugs targeting GABA transporters other than GAT1 might offer some therapeutic advantage over GAT1 selective inhibitors. Furthermore, it is particularly interesting that several recently defined GABA transport inhibitors have been demonstrated to display a preferential selectivity for the astrocytic GAT1 transporter. That cellular heterogeneity of GAT1 plays a role in the control of CNS function is confirmed by the demonstration that inhibition of astrocytic GABA uptake is highly correlated to anticonvulsant activity. At the present time, a functional role for the other GABA transporters is less well defined. However, recent findings have suggested a role for the mouse GAT2 (homologous to the human betaine transporter) in the control of seizure activity. In these studies, the non-selective GAT1 and mouse GAT2 transport inhibitor EF1502 (N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) was found to exert a synergistic anticonvulsant action when tested in combination with the GAT1 selective inhibitors tiagabine and LU-32-176B (N-[4,4-bis(4-fluorophenyl)-butyl]-3-hydroxy-4-amino-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol). Additional studies will be required to define a role for the other GABA transporters and to further identify the functional importance of their demonstrated cellular and regional heterogeneity. A summary of these and other issues are discussed in this brief review.