title: Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs.
abstract: Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.
authors.affiliation: Department of Psychiatry-Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-Shreveport Shreveport, LA, USA.
authors.forename: Donard S
authors.initials: DS
authors.lastname: Dwyer
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center-Shreveport Shreveport, LA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Aamodt
authors.affiliation: Department of Psychiatry, Harvard Medical School Boston, MA, USA ; Mailman Research Center, McLean Hospital Belmont, MA, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Cohen
authors.affiliation: Mailman Research Center, McLean Hospital Belmont, MA, USA ; Department of Neurology-Department of Psychiatry, McLean Hospital, Harvard Medical School Belmont, MA, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Buttner
keywords: Caenorhabditis elegans; anesthetics; antidepressants; antipsychotics; drug discovery; ethanol