David Janowsky:Cholinergic muscarinic mechanisms in depression and mania
Max Fink’s comment
My studies with anticholinergic compounds showed me that drugs that inhibit brain acetylcholine reversed the mood benefits of ECT. The elevated levels of brain acetylcholine associated with recovery in mood and thought seemed sufficient to justify what in 1962 I described as a cholinergic theory. I argued that seizures increased the brain levels of acetylcholine and cholinesterases and that these changes altered neuroendocrine functions, mainly of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes. This hypothesis was consistent with the ongoing enthusiasm for changes in the brain transmitters that were thought the basis for the changes in behavior associated with psychotropic drugs. (Fink 1967).
Cholinergic theory
My interest in the effects of psychoactive drugs on the EEG led me to study the effect of drugs on the ECT process (Fink, Don, Itil et al. 1966). A colleague, Herman Denber, interested me in studying the behavioral effects of diethazine, an experimental anticholinergic drug that had its action in blocking acetylcholine stimulation. The chemical was a new moiety created in industry with the hope that it might have clinically favorable psychoactive properties. He was unable to identify a clinical benefit, finding that patients became more disorganized and irritable. I administered diethazine to our improving ECT patients, those with signs of denial and recovery from a depressive state and with high degrees of EEG slowing. The slow waves were blocked and the records became filled with low voltage fast rhythms. Patients became irritable, anxious, agitated and again depressed, a reversion to their pre-treatment states. We inferred that the relief of depressed mood with ECT was related to increased levels of acetylcholine in the brain (Fink 1958).
George Ulett and his colleagues at Washington University had administered atropine, a potent anticholinergic drug, during the ECT treatment course and reported that it blocked EEG slow waves and elicited pre-treatment behaviors in the patients. Similar reversal of mood was also reported after injections of the experimental anticholinergic JB-329 (Ditran) and its congeners, supporting the connection between brain cholinergic levels and mood.
Much interest was shown in acetylcholine in neuroscience research in the 1950s. (Bradley and Fink 1965; Fink 1960). Free acetylcholine and acetylcholinesterases were elevated in the cerebrospinal fluid (CSF) of epileptic patients. CSF acetylcholine levels increased during ECT (Fink 1966). In cats subjected to graduated head trauma, the amount of free acetylcholine and cholinesterases in the CSF increased with the severity of the trauma. Again, my hubris allowed me to picture the physiologic consequences of induced seizures as similar to those of head trauma.
I imagined that induced seizures, like cerebral trauma and epileptic seizures, altered cerebral permeability increasing free acetylcholine and cholinesterases in the brain, slow EEG frequencies and increase amplitudes and rhythmic bursts. I pictured these biochemical changes as the basis for the behavioral effects we were seeing with ECT.
(Itil and Fink 1966).
References:
Bradley P, Fink M, editors. Anticholinergic Drugs and Brain Functions in Animals and Man. Progress in Brain Research, Vol. 28, Elsevier, Amsterdam, 1965; pp. 375.
Fink M. Effect of anticholinergic agent, Diethazine, on EEG and behavior: significance for theory of convulsive therapy. AMA Arch NeurPsych. 1958; 80(3):380-7.
Fink M. Effect of anticholinergic compounds on post-convulsive electroencephalogram and behavior of psychiatric patients. Electroenceph. Clin. Neurophysiol. 1960; 12:359-69.
Fink M. Cholinergic aspects of convulsive therapy. J. Nerv. Ment. Dis., 1966; 142:475-84.
Fink M. Anticholinergic drugs and brain function in animals and man. In: Brill H, editor. Neuro-Psycho-Pharmacology (Neuropsychopharmacology), Excerpta Medica, Elsevier, Amsterdam, 1967; pp. 374-90.
Fink M, Don A, Itil T, Stallings A, Holden C. Trifluperidol in the treatment of psychosis. Observations suggestive of anticholinergic activity at higher dosages. J. New Drugs, 1966; 6:174-81.
Itil T, Fink M. Anticholinergic drug induced delirium: experimental modification, quantitative EEG and behavioral correlations. J Nerv Ment Dis. 1966;143(6):492-507.
May 7, 2020