Abstract
The predictive value of currently available preclinical models for the selection of non-dopaminergic antipsychotic agents is unknown. Although devoid of direct antidopaminergic activity, MDL 100,907 has demonstrated activity in a wide-range of paradigms believed to indicate antipsychotic efficacy. In electrophysiological tests, acute administration of MDL 100,907 reverses amphetamine-induced slowing of A10 dopaminergic neurons and blocks MK-801-induced increases in firing without altering basal firing rates. Chronic administration of MDL 100,907 decreases A10 activity without affecting A9 cell firing. Neurochemically, MDL 100,907 antagonizes the MDMA-induced synthesis and release of striatal dopamine without affecting basal dopamine turnover in either the striatum or nucleus accumbens. In contrast, an increase in dopamine release in the medial prefrontal cortex is observed following administration of MDL 100,907. Although inactive in behavioral tests of extrapyramidal side-effect liability, MDL 100,907 dose-dependently reverses amphetamine-stimulated locomotor activity in mice or rats. Deficits in sound-induced prepulse inhibition produced by excessive serotonergic activity are normalized by MDL 100,907 as are amphetamine-induced deficits in latent inhibition. Based on this profile, clinical evaluation of MDL 100,907 as an antipsychotic agent will not only provide insight into the role of the serotonergic system in schizophrenia but also into the predictive validity of our preclinical models of the disorder.
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Schmidt, C., Kehne, J., Moser, P. et al. Preclinical Antipsychotic Activity of The Selective 5-HT2 Antagonist, MDL100,907. Neuropsychopharmacol 11, 282 (1994). https://doi.org/10.1038/sj.npp.1380201
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DOI: https://doi.org/10.1038/sj.npp.1380201