EARLY studies of insulin shock, particularly those by HIMWICH and his collaborators, showed that profound hypoglycaemia is accompanied by a decreased cerebral uptake of glucose and of oxygen from the blood stream. HIMWICH (1951) reviewed these studies and cited much evidence indicating that the behavioural and electrographic manifestations of hypoglycaemia are related to the reduced supply of glucose to the brain and the consequent decrease in available oxidative energy. More recently, GEIGER (1958) and his coworkers found that the perfused brain of the cat is able to function for more than 1 hr without exogenous glucose if a high perfusion rate is maintained ; this finding suggests that the brain can utilize endogenous non-carbohydrate substrates and that hypoglycaemic symptoms are due in part to the accumulation of toxic breakdown products of these substrates. ABOOD and GEIGER (1955) found decreases in the protein, lipid and nucleic acid contents of the perfused cat brain deprived of glucose and an associated accumulation in the perfusing blood of small quantities of nitrogenous substances, especially GABA, glutathione, glutamate and creatine. On the other hand, SAMSON, DAHL, DAHL and HIMWICH (1959) found that insulin shock did not significantly decrease the cerebral proteins in cats, and DAWSON (1950) made the same observation in rats.A number of other cerebral constituents are known to undergo quantitative changes during hypoglycaemia. These include glycogen, acid-soluble phosphates, and certain of the free amino acids and related compounds. Some of these substances represent possible sources of limited amounts of energy, either as oxidative substrates or as phosphorylated intermediates, while others may occur as breakdown products of proteins, lipids, or other substrates. Pertinent reports are cited in subsequent sections of this paper; in general, these chemical changes have not been studied in temporal relation to the development of electrographic abnormality.We have attempted to follow simultaneously the progression of the electrographic and a number of chemical changes in insulin shock, and their reversal on termination of the hypoglycaemia. E X P E R I M E N T A LThe experiments were done on adult male dogs weighing 8-23 kg. Food was withheld for a period of 18-24 hr, after which the cranium was exposed and opened and most of the calvarium was removed, the dura mater remaining intact. Preparation was made for electrographic recording from three cortical areas and for freezing the brain in situ with liquid air. Blood pressure was measured from a cannulated femoral artery in the final stages of the experiment. The details of these procedures have been described (TEWS, CARTER, ROA and STONE, 1963).

Food intake, growth, plasma and brain amino acid, and brain serotonin and 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations were measured in rats fed low protein diets containing disproportionate amounts of large neutral amino acids (LNAA) devoid of tryptophan or histidine (tryptophan or histidine imbalance). Five-day food intakes and weight gains of rats fed the imbalanced diets were depressed. The concentration of the limiting amino acid was low in brains of rats fed diets containing LNAA that compete with either tryptophan or histidine for entry into brain. Correlations were observed between the brain concentrations of most individual LNAA and either the ratios of the plasma concentration of that LNAA to the sum of the other LNAA, or the predicted rates of influx of that LNAA. Cumulative food intakes were correlated with brain concentrations of the limiting amino acid, tryptophan or histidine. Food intakes were not consistently correlated with concentrations of serotonin and 5-HIAA because these compounds were altered only in brains of rats in the tryptophan study. Competition among amino acids for uptake into brain appears to be involved in the feeding response of the rat to dietary disproportions of amino acids, but this response is not directly related to changes in brain concentrations of serotonin and 5-HIAA.

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Threonine entry into brain is altered by diet-induced changes in concentrations of plasma amino acids, especially the small neutrals. To study this finding further, we compared effects of various amino acids (large and small neutrals, analogues, and transport models) on transport of threonine and phenylalanine across the blood-brain barrier. Threonine transport was saturable and was usually depressed more by natural large than small neutrals. Norvaline and 2-amino-n-butyrate (AABA) were stronger competitors than norleucine. 2-Aminobicyclo[2.2.1]heptane-2-carboxylate (BCH), a model in other preparations for the large neutral (L) system, and cysteine, a proposed model for the ASC system only in certain preparations, reduced threonine transport; 2-(methylamino)isobutyrate (MeAIB; a model for the A system for small neutrals) did not. Phenylalanine transport was most depressed by cold phenylalanine and other large neutrals; threonine and other small neutrals had little effect. Norleucine, but not AABA, was a strong competitor; BCH was more competitive than cysteine or MeAIB. Absence of sodium did not affect phenylalanine transport, but decreased threonine uptake by 25% (p less than 0.001). Our results with natural, analogue, and model amino acids, and especially with sodium, suggest that threonine, but not phenylalanine, may enter the brain partly by the sodium-dependent ASC system.

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