Pharmacological Effects Produced by Intracerebral Injection of Drugs in the Conscious Mouse

Abstract

A method has been described for the study of the central effects produced by the intracerebral injection of drugs in the unanaesthetized mouse. The effects observed were in good agreement with those obtained after similar injections in cats, dogs and human beings. After intracerebral injection, drugs of diverse structure produced certain generalized effects: changes in positioning of the tail, stupor, hyperexcitability and tachypnoea; Both acetylcholine and methacholine produced an akinetic seizure and depression, but the latter compound also caused lacrimation and salivation. Atropine produced piloerection, increased sensitivity to sound and touch, clonic convulsions and scratching, whereas hexamethonium caused Parkinsonian-like muscle tremors and peripheral vasodilatation. After adrenaline, hyperexcitability, exophthalmos, stupor and death from pulmonary oedema were observed, but (+)-methylamphetamine produced only piloerection and exaggerated activity in response to sound and touch. Ergotamine caused a decreased sensitivity to sound and touch, micturition, and stupor, while ergometrine caused clonic convulsions, piloerection, defaecation and stupor. There is much current interest in the pharmacological effects observed after the administration of drugs into the brain of conscious animals. Such procedures give a better estimation of the central actions of drugs because diffusion through the blood-brain barrier is not involved. Furthermore, the doses required to produce an effect by this mode of administration are, in general, much less than those required by other routes. Feldberg and Sherwood (1953aSherwood ( and b, 1954aSherwood ( and b, 1955 have approached the problem by injecting various drugs into the lateral ventricles of cats by an implanted cannula. A similar technique has been used in dogs (Haley and Weinberg, 1955; Haley and Dickinson, 1956; Haley and McCormick, 1956). However, such animal preparations are too expensive for routine screening experiments, although they are useful for exploring sites of central activity as distinguished from peripheral ones. As a possible solution for the problem of screening for central activity, we have devised a simple method using direct intracerebral injection in the mouse.METHODS AND MATERIALS Two hundred and fifty mice (strain CF 1) of either sex, weighing 20 to 25 g. each, were used. Physiological saline solutions of the drugs studied were injected into groups of ten mice at each dose used. The animal was grasped firmly by the loose skin behind the head. The skin was pulled taut. A j in., 27 gauge hypodermic needle attached to a 0.25 ml. syringe was inserted perpendicularly through the skull into the brain and 0.01 to 0.05 ml. of solution was injected. The site of injection was 2 mm. from either side of the midline on a line drawn through the anterior base of the ears (Fig. 1). For ascertaining the areas in the brain ventricular system into which the drugs penetrated, 0.05 ml. of a 1:10 dilution of Indian ink was injected, and the brains were sectioned and...

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