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When administered to immature animals, it is known to cause apoptotic neurodegeneration in several regions, and this is followed by olanzapine\u2010sensitive, schizophrenia\u2010like behaviors in late adolescence and adulthood. Clarification of its mechanism of action could yield data that would help to inform the treatment of schizophrenia. In our initial experiments, we found that \u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazoleproprionic acid (AMPA) inhibited PCP\u2010induced apoptosis in organotypic neonatal rat brain slices in a concentration\u2010dependent and 6\u2010cyano\u20107\u2010nitroquinoxaline\u20102,3\u2010dione\u2010sensitive manner. Calcium signaling pathways are widely implicated in apoptosis, and PCP prevents calcium influx through NMDA receptor channels. We therefore hypothesized that AMPA could protect against this effect by activation of voltage\u2010dependent calcium channels (VDCCs). In support of this hypothesis, pretreatment with the calcium channel blocker cadmium chloride eliminated AMPA\u2010mediated protection against PCP. Furthermore, the L\u2010type VDCC inhibitor nifedipine (10 \u00b5M) fully abrogated the effects of AMPA, suggesting that L\u2010type VDCCs are required for AMPA\u2010mediated protection against PCP\u2010induced neurotoxicity. Whereas the P\/Q\u2010type inhibitor \u03c9\u2010agatoxin TK (200 nM) reduced AMPA protection by 51.7%, the N\u2010type VDCC inhibitor \u03c9\u2010conotoxin (2 \u00b5M) had no effect. Decreased AMPA\u2010mediated protection following cotreatment with K252a, a TrkB inhibitor, suggests that brain\u2010derived neurotrophic factor signaling plays an important role. By analogy, these results suggest that activation of L\u2010type, and to a lesser extent P\/Q\u2010type, VDCCs might be advantageous in treating conditions associated with diminished NMDAergic activity during early development. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jnr.23446","type":"journal-article","created":{"date-parts":[[2014,7,4]],"date-time":"2014-07-04T05:14:03Z","timestamp":1404450843000},"page":"1785-1791","source":"Crossref","is-referenced-by-count":5,"title":["\u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazoleproprionic acid receptor activation protects against phencyclidine\u2010induced caspase\u20103 activity by activating voltage\u2010gated calcium channels"],"prefix":"10.1002","volume":"92","author":[{"given":"Jennifer M.","family":"Timpe","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology University of Texas Medical Branch Galveston 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