Journal
PHARMACOLOGICAL RESEARCH
Volume 54, Issue 5, Pages 361-372Publisher
ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2006.07.002
Keywords
antipsychotic drugs; calmodulin; developmental toxicity; dopamine; serotonin
Categories
Funding
- NHLBI NIH HHS [HL84926] Funding Source: Medline
- NIMH NIH HHS [MH68385] Funding Source: Medline
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Antipsychotic drugs may produce adverse effects during development in humans and rodents. However, the extent of these effects has not been systematically characterized nor have molecular mechanisms been identified. Consequently, we sought to evaluate the effects of an extensive panel of antipsychotic drugs in a model organism, Caenorhabditis elegans, whose development is well characterized and which offers the possibility of identifying novel molecular targets. For these studies, animals were grown from hatching in the presence of vehicle (control) or antipsychotic drugs over a range of concentrations (20-160 mu M) and growth was analyzed by measuring head-to-tail length at various intervals. First-generation antipsychotics (e.g., fluphenazine) generally slowed growth and maturation more than second-generation drugs such as quetiapine and olanzapine. This is consistent with in vitro effects on human neuronal cell lines. Clozapine, a second-generation drug, produced similar growth deficits as haloperidol. Converging lines of evidence, including the failure to rescue growth with high concentrations of agonists, suggested that the drug-induced delay in development was not mediated by the major neurotransmitter receptors recognized by the antipsychotic drugs. Moreover, in serotonin-deficient tph-1 mutants, the drugs dramatically slowed development and led to larval arrest (including dauer formation) and neuronal abnormalities. Evaluation of alternative targets of the antipsychotics revealed a potential role for calmodulin and underscored the significance of Ca2+-calmodulin signaling in development. These findings suggest that antipsychotic drugs may interfere with normal developmental processes and provide a tool for investigating the key signaling pathways involved. (c) 2006 Elsevier Ltd. All rights reserved.
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