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Pharmacological analysis of EEG "activation" Ling, George McDonald

Abstract

The past decade has witnessed an intense interest in the influence of drugs and metabolic substances upon EEG "activation" and arousal mechanisms, mediated by the reticular activating system of the brain stem. Numerous pharmacological agents produce variations of the electrical activity of the brain. Analysis of their effects has suggested that the reticular activating system is an area wherein numerous drugs may act, and point to its multineuronal, polysynaptic character as playing a major role in central drug action. A technique has been developed which lends itself well to the study of the direct actions of drugs upon the various components of the reticular activating system of the brain stem. The experimental analysis of EEG "activation" requires the presence of a well deactivated background pattern. Observations made in the cat demonstrate that partial trigeminalectomy, cervical dorsalectomy and low cervical transection produce a preparation in which the resting EEG regularly manifests maximal deactivation. A permanent catheter inserted through the right subclavian artery and into the innominate artery so that its tip is positioned at the origin of the two carotids, has furnished a means for simultaneous bilateral distribution of injected drugs to the brain without embarrassing flow in the carotid arteries. The advantages of this technique include (a) an intact brain stem, (b) the maintenance of adequate spontaneous respiratory and circulatory states, and (c) the ability to perform various operative procedures without the necessity for extraneous pharmacological agents (anaesthetics, muscle relaxants), which may themselves have complicating effects on the EEG. In this preparation adrenergic and cholinergic agents as well as histamine and serotonin all produced prompt, short-lasting and reproducible EEG "activation" in low doses following direct intra-innominate administration. In "equi-activating" doses, isoproterenol is the most potent EEG activating catechol adrenergic amine and norepinephrine the least potent, with epinephrine occupying an intermediate position. Amphetamine and eserine both produce long-lasting EEG "activation", with amphetamine having a much shorter latency than eserine. Clear differentiation between the EEG effects resulting from direct drug-induced influences and those which may occur over reflex pathways has been demonstrated in preparations with bilateral carotid sinus denervation. Complete temporal independence is shown between the onset and termination of the actions of "activating" agents introduced directly by intra-innominate administration and the vascular effects of these agents as reflected in blood pressure alterations. Partial destruction in the tegmentum rostral to ponto-mesencephalic junction produces an increase in threshold for adrenergic EEG activation. Unilateral lesions which destroy most or all of the mesencephalic-tegmentum abolish adrenergic-induced activation in the ipsi-lateral cortex but do not affect cholinergic activation. Results obtained with various synaptic blocking agents have suggested the possible existence in the brain of three types of receptors capable of converging on the final pathway for EEG "activation"; one responsive to cholinergic compounds and blocked by atropine; one responsive to serotonin and blocked only by chlorpromazine and atropine; and one responsive to histamine and the short-acting adrenergic amines and blocked by phenoxybenzamine as well as chlorpromazine and atropine. The responses of the adrenoceptive components in the reticular activating system of the brain stem are not identical with those of any other known adrenergic receptors. This observation emphasizes the difficulty in attempts to classify receptors into a few clearly defined and discrete categories.

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