1 The effects on the high pressure neurological syndrome (HPNS) of drugs which facilitate -y-aminobutyric acid (GABA) transmission were investigated. Threshold pressures for the onset of the behavioural signs of the HPNS in mice -tremors and convulsions were established. 2 Flurazepam hydrochloride 20 and 10 mg/kg and sodium valproate 800 and 400 mg/kg substantially raised the threshold pressures for both tremor and convulsions. 3 Amino-oxyacetic acid 35 and 25 mg/kg and diaminobutyric acid 600 mg/kg also significantly increased the thresholds. Muscimol 1 mg/kg (and 150 ng i.c.v.) was ineffective at non-toxic doses. 4 These effects paralleled the drugs' ability to raise the convulsion threshold to intravenous infusion of bicuculline in mice. 5 These results demonstrate that drugs with actions more selective than those of the general anaesthetics are effective against the HPNS. It is also possible that there is a GABAergic component to the effects of general anaesthetics on the HPNS.

The effects of the benzodiazepine antagonist Ro 15-1788 20 mg kg-1 after "general anaesthetic" doses of several benzodiazepines were studied in mice, in order to determine if the effects of the latter were attributable to an action at benzodiazepine receptors. Male CDI mice were used and the end-points for anaesthesia were loss of the righting reflex and loss of the foot pinch reflex. The effects of midazolam, and to a lesser extent those of chlordiazepoxide and of diazepam on these reflexes, were antagonized partially by Ro 15-1788. When the antagonist was given after high doses of flurazepam, convulsions were produced. Calculation of the likely membrane concentrations of the benzodiazepines showed that these fitted the lipid solubility correlation for general anaesthesia. Ro 15-1788 did not decrease the lethal effects of the benzodiazepines. With flurazepam, chlordiazepoxide and diazepam it caused signs of hyperexcitability, which in the case of flurazepam led to the death of the animals.

The application of high pressure in vivo causes a hyperexcitability syndrome involving tremors and convulsions. Drugs that potentiate GABA transmission protect animals against this syndrome. It is possible that changes in gamma-aminobutyric acid (GABA) transmission may underlie the hyperexcitability. We have therefore investigated the effects of pressure on the components of GABA transmission in vitro. After incubation with [3H]GABA, hemisected frog spinal cords were superfused inside a pressure chamber and perfusate fractions were collected every 10 min. Helium, at 50 or 100 atm, did not alter the spontaneous release of GABA, but if electrical stimulation had been applied previously, then pressure caused a prolonged increase in GABA release. Helium at 50 atm did not alter the evoked release during electrical stimulation, but at 100 atm this was increased. This increase was smaller in the absence of calcium. No corresponding changes in [14C]urea efflux were seen, suggesting that the effects were not due to nonselective membrane permeability changes. The results are consistent with the known effects of pressure on neuronal activity, such as repetitive firing, but they do not suggest a selective action on the GABA release process.

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