Anticonvulsive evaluation of THIP in the murine pentylenetetrazole kindling model: lack of anticonvulsive effect of THIP despite functional δ-subunit-containing GABA A receptors in dentate gyrus granule cells.

THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is a GABA(A) receptor agonist with varying potencies and efficacies at delta-subunit-containing receptors. More importantly, THIP acts as a selective superagonist at gamma-subunit-containing receptors (delta-GABA(A)Rs) at clinically relevant concentrations. Evaluation of THIP as a potential anticonvulsant has given contradictory results in different animal models and for this reason, we reevaluated the anticonvulsive properties of THIP in the murine pentylenetetrazole (PTZ) kindling model. As loss of delta-GABA(A)R in the dentate gyrus has been associated with several animal models of epilepsy, we first investigated the presence of functional delta-GABA(A) receptors. Both immunohistochemistry and Western blot data demonstrated that delta-GABA(A)R expression is not only present in the dentate gyrus, but also the expression level was enhanced in the early phase after PTZ kindling. Whole-cell patch-clamp studies in acute hippocampal brain slices revealed that THIP was indeed able to induce a tonic inhibition in dentate gyrus granule cells. However, THIP induced a tonic current of similar magnitude in the PTZ-kindled mice compared to saline-treated animals despite the observed upregulation of delta-GABA(A)Rs. Even in the demonstrated presence of functional delta-GABA(A)Rs, THIP (0.5-4mg/kg) showed no anticonvulsive effect in the PTZ kindling model using a comprehensive invivo evaluation of the anticonvulsive properties.