NEW EFFECTS OF GABA(B) RECEPTOR ALLOSTERIC MODULATOR RAC-BHFF ON AMBIENT GABA, UPTAKE/RELEASE, EM AND SYNAPTIC VESICLE ACIDIFICATION IN NERVE TERMINALS

摘要

Positive allosteric modulators of GABA(B) receptors have great therapeutic potential for medications of anxiety, depression, etc. The effects of recently discovered modulator rac-BHFF on the key characteristics of GABAergic neurotransmission were investigated in cortical and hippocampal presynaptic nerve terminals of rats (synaptosomes). The ambient level of [H-3] GABA that is a balance between release and uptake of the neurotransmitter increased significantly in the presence of rac-BHFF (at concentrations 10-30 mu M). The initial velocity of synaptosomal [H-3] GABA uptake was suppressed by the modulator. In the presence of GABA transporter blocker NO-711, it was shown that rac-BHFF increased tonic release of [H-3] GABA from synaptosomes (at concentrations 3-30 mu M). Rac-BHFF within the concentration range of 0.3-30 mu M did not enhance inhibiting effect of (+/-)-baclofen on depolarization-induced exocytotic release of [H-3] GABA. Rac-BHFF (0.3-30 mu M) caused dose-dependent depolarization of the plasma membrane and dissipation of the proton gradient of synaptic vesicles in synaptosomes that was shown in the absence/ presence of GABA(B) receptor antagonist saclofen using fluorescent dyes rhodamine 6G and acridine orange, respectively, and so, the above effects of rac-BHFF were not associated with the modulation of presynaptic GABA(B) receptors. Therefore, drug development strategy of positive allosteric modulation of GABA(B) receptors is to eliminate the above side effects of rac-BHFF in presynapse, and vice versa, these new properties of rac-BHFF may be exploited appropriately. (C) 2015 Published by Elsevier Ltd. on behalf of IBRO.