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A previous investigation 1 dealt with the action of cholinergic drugs and of atropine on the electrical activity of the rabbit brain. It was found that acetylcholine (ACh) produces a transitory change of the brain electrical activity identical with the alerting reaction evoked by a peripheral stimulus or direct stimulation of the midbrain reticular substance.2 Isofluorophate (diisopropyl fluorophosphate; DFP), a powerful anticholinesterase agent, induces a long-lasting and continuous electroencephalographic pattern of alertness. On the other hand, atropine prevents all electroencephalographic alerting reactions, no matter how elicited. The pattern of alertness is due to the setting into activity of those mesodiencephalic structures with diffuse projections over the entire cortex, such as the midbrain reticular substance of Moruzzi and Magoun 2 and the thalamic diffuse projection system of Jasper.3 It seems that cholinergic drugs exert a primary excitation on the mesodiencephalic system, while atropine enforces a primary paralysis of the same system. We suggested in our previous publication1 that the site of action of cholinergic and anticholinergic drugs is From the located at the mesodiencephalic level. We also formulated the hypothesis that a cholin¬ ergic mechanism is involved in the function of the activating system because of the oppo¬ site effects of cholinergic and anticholinergic drugs upon it. Against these hypotheses objections could be raised in the form of alternative explanations. First of all, the effect of the drugs in question might be sec¬ ondary to their parasympathetic action on cerebral blood vessels. In fact, Darrow's * hypothesis of a parasympathetic regulation of the electrical activity of the brain suggests that the desynchronization of the brain waves produced by cholinergic drugs is secondary to the dilatation of cerebral blood vessels.Beside the effect on these vessels, there is the possibility that cholinergic drugs stimu¬ late peripheral receptors directly,f so that a flow of afferent impulses could reach the brain from the periphery and produce the alerting effect. Still another possibility is the indirect feedback of afferent impulses from smooth muscles, glands, blood vessels, and striated muscles, a secondary result of the muscarinic or nicotinic action of cholin¬ ergic drugs.To test our hypothesis that the mechanism of action of the parasympathomimetic and parasympatholytic drugs is central, it seemed necessary to investigate whether or not the drugs were still effective after the interrup¬ tion of all afferent pathways. It was also im¬ portant to determine the relationship of changes in brain circulation to the phe¬ nomenon of electroencephalographic alerting. * References 4 through 7. \ s=d\ References 8 and 9.Downloaded From: http://archneurpsyc.jamanetwork.com/ by a University of Iowa User on 06/01/2015