Looking at Lithium: Molecular Moods and Complex Behaviour
Abstract
Lithium and other mood-stabilizing drugs are used for the management of bipolar mood disorders and, to a lesser extent, for augmentation of other psychoactive drugs. Lithium also has neuroprotective properties that may be useful for treatment of neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis. Over the years, lithium has been shown to inhibit inositol monophosphatases and glycogen synthase kinase 3, but the relevance of such enzyme inhibition to the therapeutic effects of lithium has remained difficult to assess. Here, we provide an overview of recent advances in the identification of molecular mechanisms involved in the regulation of behavior by lithium. We also highlight recent findings suggesting that lithium could exert some of its behavioral effects by acting on a dopamine receptor regulated signaling complex composed of Akt, protein phosphatase 2A, and the multifunctional protein scaffold beta-arrestin 2.
Since its approval in 1970 for the treatment of bipolar illness, lithium has become a commonly prescribed mood stabilizer, with use in depression and psychotic disorders and potential use in neurodegenerative disorders such as Alzheimer disease. The predominant explanation for lithium’s actions (e.g., in FDA labeling) was for many years limited to alterations in sodium transport in excitable cells and a “shift” in catecholamine metabolism. Remarkably, specific enzyme activities were subsequently identified as targets of the simple cation, and the roles of these and other proteins in psychiatric disease were corroborated as genomic data and animal models of mood became available. New insights into catecholamine signaling, concerning the specificities of receptor subtypes and novel modalities of receptor signaling, continue to broaden our understanding of lithium’s actions. In some instances, lithium may affect mood-regulating enzymes that normally utilize magnesium as a cofactor; protein–protein interactions that control neuronal receptor pathways also appear to be subject to disruption by lithium. These insights have implications not only for the development of new psychotropic medicines, but also for our understanding of mood and behavior as functions of discrete molecular interactions.
- © American Society for Pharmacology and Experimental Theraputics 2008
