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Review ARTICLE

Front. Pharmacol., 28 July 2014 | http://dx.doi.org/10.3389/fphar.2014.00177

Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs

Donard S. Dwyer1*, Eric Aamodt2, Bruce Cohen3,4 and Edgar A. Buttner4,5
  • 1Department of Psychiatry–Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
  • 2Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, LA, USA
  • 3Department of Psychiatry, Harvard Medical School, Boston, MA, USA
  • 4Mailman Research Center, McLean Hospital, Belmont, MA, USA
  • 5Department of Neurology–Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA

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.

Keywords: anesthetics, antidepressants, antipsychotics, drug discovery, ethanol, Caenorhabditis elegans

Citation: Dwyer DS, Aamodt E, Cohen B and Buttner EA (2014) Drug elucidation: invertebrate genetics sheds new light on the molecular targets of CNS drugs. Front. Pharmacol. 5:177. doi: 10.3389/fphar.2014.00177

Received: 23 April 2014; Accepted: 09 July 2014;
Published online: 28 July 2014.

Edited by:

Adrian Preda, University of California, Irvine, USA

Reviewed by:

Charles H. Large, Autifony Therapeutics Limited, Italy
Enrico Sanna, University of Cagliari, Italy

Copyright © 2014 Dwyer, Aamodt, Cohen and Buttner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Donard S. Dwyer, Department of Psychiatry–Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center-Shreveport, 1501 Kings Highway, Shreveport, LA, USA e-mail: ddwyer@lsuhsc.edu