THE EFFECT OF SODIUM‐n‐DIPROPYL ACETATE ON γ‐AMINOBUTYRIC ACID‐DEPENDENT INHIBITION IN THE RAT CORTEX AND SUBSTANTIA NIGRA IN RELATION TO ITS ANTICONVULSANT ACTIVITY

Abstract

1 We have examined the time course of the anticonvulsant property of valproate sodium on electroshock-induced convulsions in rats and a comparison of this has been made with the action of the drug on single unit activity in the rat brain. 2 Intraperitoneal valproate sodium (100 to 400 mg/kg) protected rats from electroshock-induced convulsion. This effect was dose-dependent, the latency of the effect decreasing as a function of dose from 5 to 2 min.3 The time course of this anticonvulsant property was paralleled by a pronounced inhibition of the spontaneous firing rate of cortical and nigral neurones, following intraperitoneal administration of valproate sodium (100 to 400 mg/kg). 4 The inhibitory action of microiontophoretically applied y-aminobutyric acid (GABA) and muscimol on the firing rate of cortical neurones was potentiated within 1 to 3 min of microiontophoretic application of valproate sodium. In contrast, the inhibitory action of glycine on cortical neurones was unaffected during the microiontophoretic application of valproate sodium. 5 Microiontophoretically applied valproate sodium also potentiated inhibitory responses to GABA in rats which had received 100 mg/kg of a GABA-transaminase inhibitor, gabaculine, i.p. 16 h previously. 6 The duration of trans-synaptic inhibitory responses recorded in the substantia nigra and cortex following submaximal electrical stimulation of the striatum and cortex respectively was, in general, unaffected by either intraperitoneal or local application of valproate sodium. 7 These observations are discussed in terms of the mechanisms underlying the rapid onset of the anticonvulsant properties of valproate sodium.

The effects of chlormethiazole on single unit activity in rat brain; interactions with inhibitory and excitatory neurotransmitters

“…Potentiation of GABA-mediated inhibition has also been shown for benzodiazepines and for barbiturates (Macdonald & Barker, 1979, Alger & Nicoll, 1982, for sodium valproate (Gent & Phillips, 1980;Kerwin, Olpe & Schmutz, 1980) and for phenytoin (Ayala, Johnston, Lin & Dichter, 1977;Gent & Haigh, unpublished observations). With all of these substances glycine-mediated inhibition was not affected.…”

Drugs That Increase Γ‐aminobutyric Acid Transmission Protect Against the High Pressure Neurological Syndrome

“…It was hoped that by the use of several drugs with different mechanisms of action the involvement of GABA might be clarified. The drugs used were amino-oxyacetic acid (AOAA) which inhibits GABA-transaminase; 2,4-diaminobutyric acid (DABA) which blocks the reuptake of GABA; sodium valproate which inhibits succinic semialdehyde dehydrogenase and may also have additional postsynaptic actions (Kerwin, Olpe & Schmutz, 1980); muscimol which is an agonist at the GABA receptor and flurazepam, a benzodiazepine that potentiates transmission by action at the GABAreceptor complex.…”

The Anticonvulsant Response to Valproate in Kindled Rats Is Correlated with Its Effect on Neuronal Firing in the Substantia Nigra Pars Reticulata: A New Mechanism of Pharmacoresistance

“…Inhibition of GABAergic nigral neurons is thought to cause a disinhibition of nigral efferences in the midbrain and brainstem, which then can mediate anticonvulsant effects (Depaulis et al, 1994;Nolte et al, 2006;Gale et al, 2008). It was suggested before that suppression of spontaneous SNr neuronal firing may be one important mechanism through which VPA exerts its anticonvulsant properties (Kerwin et al, 1980;Waszczak et al, 1986;Farrant and Webster, 1989;Löscher et al, 1995;Rohlfs et al, 1996). The present findings using good and poor VPA responders substantiate this concept.…”

“…Using in vivo recordings, numerous plastic network changes were shown for basal ganglia structures including the SNr in amygdalakindled rats as a model for TLE (Gernert et al, 2004;Nolte et al, 2006;Kücker et al, 2010). Several AEDs including valproate (VPA) are known to reduce firing rates of SNr neurons in naive rats (Kerwin et al, 1980;Waszczak et al, 1986;Farrant and Webster, 1989;Löscher et al, 1995;Rohlfs et al, 1996). It was discussed that this may be an important mechanism through which some AEDs exert their anticonvulsant properties.…”