This paper concerns hyperglycaemia produced by drugs injected into the cannulated lateral cerebral ventricle, or intracisternally. Most experiments were performed on rabbits, but a few were done on cats. A difference between the two species was found.In rabbits intraventricular injection of a small dose of adrenaline, barbitone, or leptazol resulted in an increase in blood glucose concentration. The hyperglycaemia produced by adrenaline could be accounted for by its absorption from the cerebrospinal fluid (c.s.f.) into the blood stream; rabbits are particularly sensitive to the metabolic effects of adrenaline (Cori, Cori & Buchwald, 1930). On the other hand, injection of barbitone or leptazol induced a hyperglycaemia of central origin mediated by the sympathetic nervous system.In cats, which are relatively insensitive to the metabolic effect of adrenaline, the intraventricular injection of adrenaline in a dose larger than that effective in rabbits did not produce hyperglycaemia, but after its intracisternal injection there was a pronounced and sustained hyperglyeaemia. This effect has been described previously by Leimdorfer, Arana & Hack (1947), who produced hyperglycaemia by injecting intracisternally 50 ,ug adrenaline/kg. The same amount of adrenaline injected into a joint or intraperitonealiy did not raise the blood glucose concentration, so they concluded that the hyperglyeaemia was of central origin. They also concluded that the adrenaline was not absorbed into the blood stream, since it could be detected in the cerebrospinal fluid 16 hr after an intracisternal injection of 0-5 mg. METHODS

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Sodium salicylate and related compounds are widely used for their antipyretic properties. It has been suggested that the antipyresis is due to an effect on the hypothalamus, leading to increased heat loss (Barbour, 1926;Guerra and Barbour, 1943). This concept, however, does not specify what effects salicylate would be expected to have on metabolic rate.The observation of Reid (1952), when studying the changes in acid-base balance, that sodium salicylate caused a marked increase in the 0°con-sumption of the rabbit, was surprising in view of the antipyretic activity of the drug. The question arose, whether such an increase occurred in man with therapeutic doses of sodium salicylate. Denis and Means (1916) appear to have been the first to observe the effect clinically, but they did not attach any significance to it; Cochran (1952), however, clearly demonstrated that salicylate is a powerful metabolic stimulant in man.The present study was to determine whether metabolic stimulation by sodium salicylate occurs only in the whole animal, or if it is also demonstrable in isolated tissue. METHODSThe 02 consumption of liver slices from CBA mice was determined by the direct method in Warburg respirometers at 370 C., according to the procedure of Dixon (1951). Glucose-phosphate-Ringer of pH 7.40 was used as medium. It was dispensed from double strength stock solutions and finally made up to volume in the Warburg flasks with water for the control tissues, or with a solution of sodium salicylate for the treated tissues.Sufficient slices were obtained from each mouse to determine in duplicate the control rate of 02 consumption, in c.mm. 02 at N.T.P./hr./mg. dry weight of tissue (Qo2), and that in the presence of sodium salicylate.Preliminary observations were made from a concentration of sodium salicylate of 10-5M upwards. Systematic observations were then made at eight concentrations found to affect the Qo2 of the liver slices; at each of these concentrations liver slices from sixteen mice, eight of each sex, were studied.The duration of the runs was 30 min.; readings were taken at 15-min. intervals. RESULTSFor each animal, the difference between the mean control and treated rates of 02 consumption (AQo2) was obtained by subtracting the Qo2 of the salicylate treated tissue from that of the control. Therefore increased rates of 02 uptake appear as positive quantities and decreased rates as negative.

The present experiments on anaesthetized cats show that acetylcholine is released from the ventral surface of the brain. The results were obtained by perfusing the subarachnoid space with neostigmine, either from cisterna magna to fissures of Sylvius or from interpeduncular fossa to cisterna magna, and assaying the acetylcholine in the effluent.Release of acetylcholine from the surface of the brain has previously been studied only from the dorsal and lateral aspects of the cerebral cortex, and the technique used was to place eserinized fluid, in a small Perspex ring, on the surface of the cortex, and to determine the amounts of acetylcholine diffusing into this fluid during a given time (MacIntosh & Oborin, 1953;Mitchell, 1963).It was shown in the preceding paper (Beleslin & Polak, 1965) that morphine depresses the release of acetylcholine into the perfused cerebral ventricles from the caudate nucleus, and the question arose whether morphine would have a similar action on other parts of the brain. Therefore, in the present experiments on perfusion of the subarachnoid space, the effect of morphine on the acetylcholine output was examined. This paper also includes observations on shivering produced by neostigmine, and on the abolition of this shivering by adrenaline. METHODSCats of 2-5-30 kg body weight were anaesthetized with either 180 mg amytal sodium, injected intraperitoneally, orychloralose, 80 mg/kg, injected intravenously, and tracheotomy was performed.Perfusion from cisterna magna to fissures of Sylvius was carried out as described by da Silva & Sproull (1964). For the inflow a fine needle was inserted through the dorsal atlanto-occipital membrane into the cisterna, and the outflow was collected in acrylic reservoirs constructed on the skull around the exposed fissures at the level of the temporoparietal sutures on both sides. The effluent was recovered from the reservoirs with a Pasteur pipette.For perfusion from the interpeduncular fossa to cisterna magna, a fine inflow cannula was inserted from the dorsal surface of the brain, through the cortex and mid-brain, into * Wellcome Research Fellow. t NATO Science Fellow.

Leimdorfer, Arana & Hack (1947) have shown that in the cat an intracisternal injection of adrenaline produces a long-lasting hyperglycaemia, which they attributed to a central action of the adrenaline. The hyperglycaemia was not reproduced by an intraperitoneal injection of adrenaline. In contrast, the hyperglycaemia produced in the rabbit by the injection of adrenaline into the lateral cerebral ventricle is fuliy accounted for by its absorption into the blood stream, since it is reproduced by intraperitoneal injection and is not affected by bilateral splanchnicotomy (Hasselblatt & Sproull, 1961). It appeared therefore that the hyperglyeaemic response of the cat to intracisternal and of the rabbit to intraventricular adrenaline might result from different mechanisms.However, the present experiments show that one difference between the two species is that, whereas in the rabbit adrenaline given byintraperitoneal injection readily elicits a hyperglycaemic response (Hasselblatt & Sproull, 1961), in the cat it does not. This is not due to a difference in the sensitivity of the two species to the metabolic action of adrenaline because, when infused intravenously, adrenaline is found to be as effective in the cat as in the rabbit. The hyperglyeaemic response of the cat to an intracisternal injection of adrenaline could therefore well be accounted for by absorption.The importance of this mechanism was established in the present experiments by the effect of bilateral splanchnicotomy on the hyperglycaemic response, but a central component, mediated by the splanchnic nerves, was also revealed.According to Leimdorfer (1950), noradrenaline given in small doses by intracisternal injection is, like adrenaline, effective in raising blood glucose concentration. If the hyperglyeaemic effect of intracisternally injected adrenaline or noradrenaline is largely due to systemic absorption noradrenaline should in this respect be the less effective, since it is well known that noradrenaline has a much weaker metabolic action than adrenaline.Previous estimates of the relative hyperglycaemic potency ofnoradrenaline vary greatly, between

In anaesthetized cats perfusion of the cerebral ventricles with an anticholinesterase provides a simple method for studying the effect of centrally active drugs on the release of acetylcholine from structures bordering the ventricular cavities. On perfusion with neostigmine from lateral ventricle to aqueduct, acetylcholine appears in the effluent and this acetylcholine is mainly derived from the caudate nucleus (Bhattacharya & Feldberg, 1958c;Beleslin, Carmichael & Feldberg, 1964); this output is reduced by morphine and chloralose, two central depressant drugs (Beleslin & Polak, 1965).The present experiments show that intravenous injections of two convulsant drugs, leptazol and strychnine, have the opposite effect, and cause an increased output of acetylcholine in the aqueductal effluent.Electrical stimulation of the caudate nucleus also leads to an increased output in the effluent. Further it is shown that the action of leptazol and strychnine is not confined to the caudate nucleus, but that these convulsant drugs have a similar action on the acetylcholine release from the cerebral cortex.Our findings are in agreement with two previous observations. First, Mitchell (1963) found in sheep that an intravenous injection of leptazol increases the release of acetylcholine from the cerebral cortex. Secondly, Mitchell & Szerb (1962) using the push-pull cannula technique of Gaddum (1961), found an increased release of acetylcholine from the caudate nucleus, on electrical stimulation of this nucleus in cats. METHODSCats of 20-2-5 kg body weight were anaesthetized with chloralose, 45-65 mg/kg, given intravenously through a cannula inserted in the femoral vein under ethyl chloride anaesthesia, and tracheotomy was performed. The femoral artery was cannulated for recording of the arterial blood pressure, using a Cambridge transducer and a Leeds and Northrop * Wellcome Research Fellow.t NATO Science Fellow.

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