SUMMARY1. Samples of cisternal cerebrospinal fluid (c.s.f.) and blood plasma have been obtained nearly simultaneously from foetal sheep of different ages, the foetus having been exteriorized and maintained in a normal state with respect to its blood gases and arterial pH. The brains were removed from these foetuses and also from foetal guinea-pigs after exsanguination.2. A comprehensive study has been made of the concentrations ofwater, chloride, sodium, potassium, calcium and magnesium in blood plasma, c.s.f. and brain from foetal sheep and in brain from foetal guinea-pigs during development in utero. Maternal arterial blood plasma, cisternal c.s.f. and brain from the sheep and brain from the guinea-pig have been analysed for comparison.3. Concentrations of the ions analysed in foetal blood plasma are similar to those found by others in the sheep and other species. In the case of calcium, the results suggest an active maintenance of the concentration of this ion in foetal plasma by the placenta.4. The chloride concentration in c.s.f. at ages between 65 days and term (147 days) averaged 1-19 times that in foetal plasma, but only 1-08 at 45-50 days; the sodium concentration in c.s.f. was also slightly reduced at this time. The increase in the c.s.f./plasma ratios for chloride and sodium appears to coincide with the first development ofthe blood-brain and bloodc.s.f. barriers to non-electrolytes.5. Magnesium was at a slightly higher concentration in c.s.f. than in plasma at all foetal ages and did not vary with age. The concentrations of potassium and calcium in c.s.f. were high at early ages and fell to reach adult concentrations after birth: the mechanisms determining the M. W. B. BRADBURY AND OTHERS concentrations of the various ions in c.s.f. develop at very different, largely independent, rates.6. The water content of the cerebral hemispheres of the foetal sheep was stable at 90 % of the wet weight till 105 days and fell thereafter. The contents of chloride, sodium and potassium followed paraboloid relations with age. Chloride and sodium reached a peak of 62 and 81 m-equiv/kg respectively between 89 and 105 days in the sheep. Potassium was at a minimum of 65 m-equiv/kg at the same time. The content of water and these electrolytes in the cerebral hemispheres of the foetal guinea-pig underwent similar changes, the maxima and minimum occurring as in the sheep at two-thirds of the total length of the pregnancy, namely 65 days in the guinea-pig. At 46 days in the guinea-pig, chloride in brain reached 53 mequiv/kg, sodium was 68 m-equiv/kg and potassium was 75 m-equiv/kg. In contrast to the sheep, no reversal ofthe sodium-potassium ratio occurred. These changes in water and electrolytes probably represent a rise, a peak and a decrease in the volume of the extracellular space of cerebral cortex, but changes in the volume occupied by a cell-type, containing much intracellular chloride and sodium, could also contribute to this phenomenon. 7. The calcium content in the cerebral hemispheres of the foetal sheep remained ...

Phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) dose-dependently inhibited veratrine-stimulated calcium influx and evoked amino acid neurotransmitter release in rat cortical slices at relatively low concentrations. The action on Ca2+ influx was in the clinical effective dose range for these anticonvulsant drugs, whereas the action on amino acid release was mostly well above this range. Neither ethosuximide (ESM) nor sodium valproate (VPA) had any effect on the veratrine-stimulated Ca2+ influx. Stimulated amino acid release was not affected by ESM, whereas VPA specifically inhibited the release of aspartate in preference to glutamate and GABA at concentrations well within the clinically effective dose range. The actions of VPA and ESM on other parameters measured were detectable only at very high concentrations, which are likely to be irrelevant in defining their clinical mode of action.

The effect of kainate on extracellular levels of amino acids in corpus striatum was investigated in vitro and in vivo, to elucidate the mechanism underlying its neurotoxicity. Kainate increased extracellular glutamate and aspartate in both striatal slices in vitro and intact striatum in vivo, as previously reported. Both in vitro and in vivo, DL-threo-3-hydroxyaspartate increased extracellular glutamate and aspartate levels (to between 150 and 200% of basal), and also enhanced their kainate-evoked release. The action of kainate in vivo was reduced by prior frontal decortication, whereas in vitro the kainate-evoked responses were only slightly reduced by tetrodotoxin, and remained above control values. These results confirm that kainate increases extracellular glutamate and aspartate, and provide evidence that this is due to synaptic release evoked by an action on receptors on glutamatergic neurone terminals. These findings may be relevant to the understanding of epilepsy.

No abstract

Hippocampal brain slices were incubated with depolarizing agents or excitatory amino acids either alone or in the presence of excitatory amino acid antagonists [omega-phosphonic alpha-aminocarboxylic acids--2-amino-4-phosphonobutyric acid (AP4), 2-amino-5-phosphonovaleric acid (AP5), or 2-amino-7-phosphonoheptanoic acid (AP7)--or gamma-D-glutamylaminomethylsulphonic acid (GAMS)] or a calcium-channel blocker, (S)-1-(3-methoxyphenyl)-3-methylaza-7-cyano-7-(3,4-dimethoxyphenyl )-8-methyl- nonane hydrochloride [(-)-D888]. The uptake of 45Ca2+ and the efflux of glutamate or aspartate induced by veratrine or high K+ was blocked (54-76%) by AP7 (IC50 46-250 microM). AP5 and AP4 were less effective. (-)-D888 (10 microM) caused 100% block of evoked 45Ca2+ uptake. Uptake of 45Ca2+ induced by exogenous glutamate, aspartate, and N-methyl-D-aspartate (NMDA) was also inhibited by AP7, whereas GAMS completely blocked the action of kainate and partially blocked that of glutamate. The action of NMDA in stimulating 45Ca2+ uptake was Mg2+-sensitive, low Mg2+ levels in the incubation medium selectively enhancing the response. It is concluded that Ca2+ uptake evoked by excitatory amino acids is receptor-mediated, and that released excitatory amino acids are responsible for a large part of the action of veratrine and high K+ in stimulating 45Ca2+ uptake.