Neural and developmental actions of lithium: A unifying hypothesis

AFRC Unit of Insect Neurophysiology and Pharmacology Department of Zoology Cambridge CB2 3EJ England tSmith Kline & French Research Ltd. The Frythe, Welwyn Hertfordshire AL6 9AR England *MRC Molecular Neurobiology Unit University of Cambridge Medical School Cambridge CB2 2QH England Lithium, with an atomic weight of 6.9, is the smallest of the alkali metals, yet this simple ion can exert a profound ef- fect on both human behavior and early embryonic devel- opment. Manic-depressive psychosis, characterized by dramatic swings in mood, can be effectively controlled by maintaining a serum level of Li+ of ~1 mM. Despite its therapeutic success, little is known about the way Li+ can modify neurotransmission within the central nervous sys- tem (CNS). Many of the proposed mechanisms have sug- gested an inhibitory effect on components of various neu- rotransmitter signaling pathways, such as cyclic AMP formation, cyclic GMP formation, G proteins, or inositol phosphate metabolism (Hallcher and Sherman, 1960; Berridge et al., 1962). Only the latter provides a plausible explanation of the Li+ conundrum, i.e., the reason this ion