TRIFLUOPERAZINE AND DIBUCAINE-INDUCED INHIBITION OF GLUTAMATE-INDUCEDMITOCHONDRIAL DEPOLARIZATION IN RAT CULTURED FOREBRAIN NEURONS

1 Glutamate receptor activation has been previously shown to result in mitochondrial depolarization and activation of the mitochondrial perm eability transition pore in cultured neurones. In this study, we chara cterized the effects of two putative permeability transition inhibitor s, namely trifluoperazine and dibucaine, on mitochondrial depolarizati on in rat intact, cultured forebrain neurones. 2 Permeability transiti on was monitored by following mitochondrial depolarization in neurones loaded with the mitochondrial membrane potential-sensitive fluorescen t indicator, JC-1. Trifluoperazine (10-20 mu M) and dibucaine (50-100 mu M) inhibited or delayed the onset of glutamate-induced permeability transition. 3 We also investigated the effects of trifluoperazine and dibucaine on neuronal recovery from glutamate-induced Ca2+ loads. Tri fluoperazine affected Ca2+ recovery in a manner similar to the mitocho ndrial Na+/Ca2+ exchange inhibitor, CGP-37157, while dibucaine had no apparent effect on Ca2+ recovery. Therefore, inhibition of permeabilit y transition does not appear to be involved in Ca2+ recovery from glut amate-induced Ca2+ loads. 4 Trifluoperazine and dibucaine did not inhi bit [H-3]-dizocilpine binding at the concentrations that prevented mit ochondrial depolarization. 5 These studies suggest that trifluoperazin e and dibucaine inhibit permeability transition in intact neurones. Tr ifluoperazine also appears to inhibit mitochondrial Na+/Ca2+ exchange. These drugs should prove to be valuable tools in the further study of the role of mitochondrial permeability transition in glutamate-induce d neuronal death.