Pharmacokinetics of clozapine and its metabolites in hippocampal HT22 cells

Heiser, Philip; Schüler-Springorum, Mareike; Schulte, E.; Hausmann, Christiane; Remschmidt, Helmut; Krieg, Jürgen-Christian; Vedder, Helmut

doi:10.1016/s0014-2999(03)02176-9

Cited by 6 publications

(1 citation statement)

References 42 publications

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“…Furthermore, mutant animals that lack AHR‐1 have PLM axons that extend past the normal termination point (Qin and Powell‐Coffman, 2004). Clozapine binds to the human aryl hydrocarbon receptor at physiologically relevant concentrations (Heiser et al, 2003; Meyer et al, 1996; Talaska et al, 2006). Thus, AHR‐1 represents an intriguing target because mutant strains lacking this receptor phenocopy the effects of clozapine on ALM migration and PLM axonal outgrowth.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic drugs alter neuronal development including ALM neuroblast migration and PLM axonal outgrowth in Caenorhabditis elegans

Donohoe

Weeks²,

Aamodt³

et al. 2008

Intl J of Devlp Neuroscience

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Antipsychotic drugs are increasingly being prescribed for children and adolescents, and are used in pregnant women without a clear demonstration of safety in these populations. Global effects of these drugs on neurodevelopment (e.g., decreased brain size) have been reported in rats, but detailed knowledge about neuronal effects and mechanisms of action are lacking. Here we report on the evaluation of a comprehensive panel of antipsychotic drugs in a model organism (Caenorhabditis elegans) that is widely used to study neuronal development. Specifically, we examined the effects of the drugs on neuronal migration and axonal outgrowth in mechanosensory neurons visualized with green fluorescent protein expressed from the mec-3 promoter. Clozapine, fluphenazine, and haloperidol produced deficits in the development and migration of ALM neurons and axonal outgrowth in PLM neurons. The defects included failure of neuroblasts to migrate to the proper location, and excessive growth of axons past their normal termination point, together with abnormal morphological features of the processes. Although the antipsychotic drugs are potent antagonists of dopamine and serotonin receptors, the neurodevelopmental deficits were not rescued by coincubation with serotonin or the dopaminergic agonist, quinpirole. Other antipsychotic drugs, risperidone, aripiprazole, quetiapine, trifluoperazine and olanzapine, also produced modest, but detectable, effects on neuronal development. This is the first report that antipsychotic drugs interfere with neuronal migration and axonal outgrowth in a developing nervous system.

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