Activity-dependent enhancement of hyperpolarizing and depolarizing γ-aminobutyric acid (GABA) synaptic responses following inhibition of GABA uptake by tiagabine

The effects of the gamma-aminobutyric acid (GABA) uptake blocker tiagabine on isolated inhibitory postsynaptic potentials (IPSPs) were examined in CA1 pyramidal cells of the rat hippocampal slice preparation. The IPSPs were elicited by either single stimuli or by high frequency (100 Hz, 200 ms) stimulation (HFS) of inhibitory interneurons. Bath applied tiagabine (20 mu M) produced little or no increase in the amplitude of IPSPs evoked by low (30-50 mu A) or high (200-400 mu A) intensity single stimuli. Only the duration of IPSPs evoked by high intensity stimuli was substantially prolonged by tiagabine, the time integral of the hyperpolarizing response being increased 3.2-fold. HFS elicited much larger fast and slow IPSPs than a single stimulus. In addition, with increments in the intensity (80-550 mu A) of HFS, a GABA, receptor-mediated depolarizing response of progressively larger amplitude appeared between, and overlapped with, the fast and slow hyperpolarizing components of the IPSP. Tiagabine application markedly increased the GABA-mediated responses evoked by both low and high intensity HFS. Increasing the intensity of HFS enhanced the drug effect. Thus, measurements of the time integral of evoked responses showed that with weak (60 mu A) HFS, tiagabine caused a 3.6-fold increase in the area of hyperpolarization while, in contrast, with strong (530 mu A) HFS, tiagabine produced a 13.5-fold increase in the depolarizing actions of GABA. Our results suggest that tiagabine, a therapeutically effective anticonvulsant, may paradoxically increase, through a GABA(A) receptor-mediated mechanism, neuronal depolarization during the high frequency discharge of neurons involved in epileptiform activity. (C) 1999 Elsevier Science B.V. All rights reserved.