Phenylethylidenehydrazine, a novel GABA-transaminase inhibitor, reduces epileptiform activity in rat hippocampal slices.
Phenylethylidenehydrazine (PEH), an analog of the monoamine oxidase inhibitor, beta-phenylethylhydrazine (phenelzine), inhibits the gamma-aminobutyric acid (GABA) catabolic enzyme GABA-transaminase and increases brain levels of GABA. GABA is the predominant fast inhibitory transmitter counteracting glutamatergic excitation, and increased neural GABA could influence a wide range of synaptic and circuit properties under both physiologic and pathophysiologic conditions. To examine the scope of these effects, we applied PEH (or vehicle) to rat hippocampal slices and measured basal glutamatergic transmission, synaptic plasticity, and epileptiform activity using extracellular field and whole cell patch clamp recordings. In vitro pre-treatment with PEH (100 microM) increased the GABA content of hippocampal slices by approximately 60% over vehicle-treated controls, but it had no effect on basal field excitatory postsynaptic potentials, tonic GABA currents, paired-pulse facilitation, or long-term potentiation. In contrast, pre-incubation with PEH caused a dose- and time-dependent reduction in epileptiform burst frequency induced by superfusion with Mg2+-free or high-K+ artificial cerebrospinal fluid. Thus, the inhibitory effects of PEH are state-dependent: hyper-excitation during epileptiform bursting was reduced, whereas synaptic transmission and plasticity were unaffected.
Duffy
S
S
Department of Physiology, University of Alberta, Edmonton, Canada.
Nguyen
P V
PV
Baker
G B
GB
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004827:Epilepsy / Q000188:drug therapy / Q000201:enzymology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D006834:Hydrazines / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D006834:Hydrazines; C444559:phenylethylidenehydrazine; D000612:4-Aminobutyrate Transaminase