THE ADMINISTRATION OF DRUGS INTO THE CEREBRAL VENTRICLES OF MONKEYS: PITUITRIN, CERTAIN PITUITARY FRACTIONS, PITRESSIN, PITOCIN, HISTAMINE, ACETYL CHOLINE, AND PILOCARPINE

¹ From the Laboratory of Svrgical Research, Harvard Medical School

It was suggested by Professor J. J. Abel in personal correspondence with Dr. Cushing and ourselves, that the pharmacological demonstration of the existence of a central parasympathetic center, located in the paraventricular nuclei of the hypothalamus, was inconclusive in so far as the supposed proof was based on the use of pituitary preparations of a relatively impure nature. Abel postulated that the unusual responses to intraventricular pituitrin (flushing, sweating, temperature drop, and fall in metabolic rate) might be due to vascular absorption of the non-hormonic substances, some of which are thought to be vasodilating bodies.

A new investigation was therefore undertaken in monkeys. The studies included (a) whole posterior lobe extract (pituitrin), (b) pituitary extracts in which the hormone (vasopressin) had been partially purified, (c) pituitary extracts composed mainly of impurities, after almost complete removal of pressor substances, (d) depressant drugs.

Injection of pituitrin into the lateral cerebral ventricles initiated prompt vasodilatation in the oral mucous membrane. This flushing response occurred within thirty to forty seconds of the injection, whereas absorption of the drug into the blood stream did not take place for three to five minutes, when cardiac retardation and drop in blood pressure occurred. Coincident with the appearance of these signs of peripheral action, vasoconstriction with attendant blanching of the mucous membrane superceded the flushing response. Because of the long pathway taken by the cerebrospinal fluid in passing from the lateral ventricles to the absorptive bodies in the arachnoidal Spaces, this striking difference in appearance time indicates that the flushing response was generated centrally by action of the drug on nervous tissue adjacent to the ventricular chambers.

The second group of studies showed that all extracts (including pitressin), which contained 20 or more pressor units per cubic centimeter, stimulated the flushing response from ventricular administration. The same extracts led only to vasoconstriction when given intravenously.

In the group with reduced vasopressin activity, it was found that an extract containing pressor unit per cubic centimeter was without action when injected into the cerebral ventricle, but led to bright vasodilatation when administered into the vein. Pitocin, an extract with less than one pressor unit per cubic centimeter produced no reaction from the ventricle, and vasodilatation followed direct injection into the blood. One extract with one pressor unit per cubic centimeter, and one which had not been assayed but was evidently of low vasopressin activity, produced disparate results: ventricular administration was occasionally attended by the flushing response, and intravenous injection led to vasodilatation in some and vasoconstriction in others.

The depressant drugs, histamine and acetyl choline, were without flushing effect when administered into the ventricle. In fact, histamine exhibited a tendency to produce the opposite effect, that of blanching. The usual vasodilatation followed intravenous injections of these drugs.

It is seen therefore that the flushing response, which is alien to the known peripheral action of the pressor principle, is yet related to the hormone when the drug is acting on brain tissue in the walls of the cerebral ventricles. It appears also that true vasodilators are ineffective when employed in the ventricles of monkeys. We conclude that the flushing response is elicited by the hormone itself or by some protein or other chemical principles which follow the same chemical pathways during fractionation as the hormone.