SUMMARY1. The hypophysiotrophic area of the rat hypothalamus was studied in vitro. The preparation remained viable for at least 3 hr and showed oxygen consumption varying between 68-9-120 ,umole/g. hr. The tissue potassium ion content (per unit wet weight) fell to about 50 % ofthe in vivo concentration during this time compared with 15 % in the presence of ouabain (104 M). Histological examination of tissue incubated for 3 hr showed variable perineuronal oedema but the nuclei were of normal appearance and none showed the pyknotic changes that would be associated with cell degeneration.2. Corticotrophin releasing hormone (CRH) in the medium pooled from five to twenty hypothalami was assayed in five to twelve rats which were median-eminence lesioned 48 hr earlier. In vitro corticosterone production of quartered adrenals was used as the end point of the assay. Regression lines of the dose-response curves for ACTH, crude CRH and different volumes of medium from electrically stimulated hypothalami were parallel.CRH output was maximal at 75 Hz and 100,uA when the square-wave pulses lasted for 1 msec. No CRH activity was found on stimulation of cerebral cortex or thalamic tissue pieces of equivalent size.3. Hypothalami taken from rats, adrenalectomized 7-14 days previously, released several-fold more CRH into the medium during electrical stimulation than the initial content of the tissue, showing that the tissue was capable of synthesizing CRH in vitro. The hypothalami taken from intact rats released considerably less CRH into the medium than tissue taken from 12 to 14 day adrenalectomized rats. The hyper-secretion of CRH observed in hypothalami taken from adrenalectomized rats was abolished by pre-treatment with 5 mg/100 g s.C. of corticosterone 24 hr before removal of the tissue. It is therefore proposed that the delayed negative feed-back action of corticosterone at the hypothalamic level is by the suppression of CRH synthesis and that the effect of secretion is secondary to the effect on synthesis.4. The presence of Ca2+ in the medium was essential for the release of CRH.5. CRH secretion increases linearly with doses of acetylcholine from 5.5 X 10-1k-5-5 X 10--14 M. Cerebral cortex incubated with acetylcholine showed no CRH activity. The effect of acetylcholine was reduced by atropine (3.5 x 10-13 M). Median eminence-pituitary stalk fragments (which contain mainly terminal axons of neurones) incubated with acetylcholine showed no CRH stimulation in the doses that activate the release of CRH using the hypophysiotrophic hypothalamus. Acetylcholine may act as a neurotransmitter at the dendritic level in the CRH neurone.

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The amount of radioactivity in brain was estimated at different times after intracarotid injection in the pentobarbital-anesthetized rat. Fifteen seconds after injection, six radiolabeled solutes minimally metabolized by brain, 3H2O , isopropanol, nicotine, antipyrine, 3-O-methyglucose, and codeine, left the brain according to first-order kinetics. Two solutes metabolized by brain, lactic acid, and heroin, behaved in a more complex fashion. The behavior of the six nonmetabolized solutes was interpreted satisfactorily by a simple model in which the brain is treated as a single compartment. From the model, uptake at 15 s as a percentage of the dose is linearly related to the permeability when the uptake is low, i.e., 30% or less. In higher uptakes blood flow becomes increasingly important. The efflux rate is similarly related to permeability and blood flow, but additionally it depends inversely on brain space. The exchanges of 3H2O, isopropanol, and nicotine were determined almost solely by blood flow and brain space. Movements of codeine and 3-O-methylglucose depended primarily on permeability and those of antipyrine on both factors.

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SUMMARYDiabetes was induced with streptozotocin in rats weighing about 160 g. These were maintained with age-matched controls for up to 14 months, blood glucose being periodically monitored. Half the diabetic and control rats received the aldose reductase inhibitor, Ponalrestat, in their diet. At 3 weeks, 6-7 months and 13-14 months, the vascular permeability in regions of brain, and in optic and sciatic nerves, were measured by maintaining radiotracers in the bloodstream -'l25-albumin (100 min), [14C]sucrose (60 min) and 1311-albumin (5 min) -followed by tissue sampling and counting at termination. 131I-albumin estimated residual intravascular plasma.Diabetes of up to 13-14 weeks caused no measurable increase in the sucrose permeability of microvessels in eight different brain regions, in optic or in sciatic nerve. At 3 weeks of diabetes, sucrose permeability in all brain regions and in optic nerve was reduced relative to that in controls. Extravascular albumin entry into different regions of brain and optic nerve was insignificant and insensitive to diabetes, except in the hypothalamus and optic nerves where it was raised with increasing duration of diabetes. In sciatic nerve, extravascular albumin distribution was markedly increased by diabetes, but sucrose permeability was not demonstrably affected. At the level used in the diet, Ponalrestat reduced the sorbitol content of diabetic sciatic nerve but did not protect again the increased permeability to albumin.