In response to severe ischemia, neurons undergo anoxic depolarization (AD), a spreading signal that propagates at 1-3 mm/min through gray matter. We have reported blockade of AD by certain σ1R ligands (SFN Abstr., 26:282.15, 2001). Here we tested haloperidol (HAL), a σR ligand and antispychotic, for its ability to block AD. We imaged cell swelling at the AD front in rat neocortical slices at 35°C. AD was evoked by 5 min bath application of 100 µM ouabain which simulates ischemia. AD was imaged as a propagating front of elevated light transmittance, arising 288 ± 90.1 sec following ouabain exposure (n=26/26 slices). Pretreatment with 30, 50 and 100 (but not 10) µM HAL blocked AD in 34 of 41 slices. Sulpiride (100 µM, 12/12) or AP-5 (50 µM, 8/8) did not block or delay AD. Moreover, cell swelling evoked by 50 µM NMDA (10/10) persisted with 50 µM HAL (14/14). Thus, HAL effects are not through antagonism of D2 or NMDA receptors but possibly through σ2R agonism. However, AD block by 50 µM HAL was not reversed by...