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The mode of action of baclofen on the physiology of the rat hippocampus was investigated by studying its effect on electrophysiological responses in the hippocampal slice preparation and by measuring biochemical parameters related to glutamate uptake, binding, and release.Baclofen inhibited, in a dose-dependent fashion, the dendritic field potentials in field CA1 produced by stimulation of the Schaffer commissural fiber system. The drug was inactive in this respect at concentrations of 10 and 100 nM but consistently reduced the amplitude of both the dendritic field potential and the population spike at a concentration of 1 pM. At a concentration of 25 PM, baclofen virtually abolished the dendritic and cell body responses to afferent stimulation. Recovery of field potentials required between 7 and 10 min following the addition of 1 pM baclofen.The levorotatory form of baclofen was much more potent in suppressing synaptic responses than was the dextrorotatory enantiomer.Baclofen, at a concentration of 5 PM, strongly antagonized the excitation of pyramidal neurons evoked by iontophoretically applied glutamate. The antagonism of the glutamate effect was much reduced when the slices were maintained in low calcium, high magnesium perfusion medium. Moreover, under low calcium conditions, baclofen did not interfere with the effects of bath-applied glutamate on antidromically elicited responses.Baclofen did not affect the Na+-dependent or Na+-independent binding of [3H]glutamate to crude synaptic membrane fractions from the hippocampus. However, at a concentration of 1 PM, it markedly inhibited potassium-induced release of [3H]glutamate from hippocampal synaptosomes.Taken together, the present results strongly suggest that baclofen suppresses synaptic responses in the Schaffer commissural fiber system of the hippocampus by blocking the release of an excitatory amino acid transmitter.The mechanism and site of action of the antispastic agent baclofen (Lioresal) are still a matter of controversy. In view of its close structural resemblance to GABA, the drug was originally thought to be a GABA agonist. However, subsequent studies found that baclofen has a low affinity for GABA binding sites (Olsen et al., 1978) and that its depressant action on cell firing is not antagonized by bicuculline (Curtis et al., 1974). While it does not appear that baclofen exerts its physiological effects via the "classical" GABA receptors, recent work has suggested that it may interact with a novel, bicucullineinsensitive GABA binding site (Bowery et al., 1979). It

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and > 6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 x 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 x 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 x 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified.(ABSTRACT TRUNCATED AT 250 WORDS)