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Asymmetry and Mood, Emergent Properties of Serotonin Regulation A Proposed Mechanism of Action of Lithium

Arnold J. Mandell, MD; Suzanne Knapp, MS
Arch Gen Psychiatry. 1979;36(8):909-916. doi:10.1001/archpsyc.1979.01780080083019.
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The purpose of this communication is to develop a model of the pathogenesis of affective spectrum disorders and their treatment and prevention with lithium; the model is based on (1) studies of baseline and drug-induced bilateral asymmetry in tryptophan and serotonin levels in rat brain mesostriatal and mesolimbic systems, (2) singlecell quantitative histochemical determinations of serotonin content in lateral median and dorsal raphe nuclei, (3) the responses of brain tryptophan hydroxylase activity to psychotropic agents, (4) in vitro studies of the kinetic properties of tryptophan hydroxylase, and (5) evidence of lateral affective specialization in human brain. The disorders are construed as diseases of regulation involving an abnormal form of brain tryptophan hydroxylase with hyperbolic substrate kinetics, possibly resulting from a hereditary defect in enzyme cooperativity or calcium metabolism or the influence of yet unidentified ligands. The abnormal enzyme kinetics would serve to amplify the functional impact of existing bilateral asymmetries


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