Massive increases in extracellular dopamine have been reported in the ischemic rodent striatum, implicating this neurotransmitter in toxic events. We have examined whether dopamine receptor antagonists are protective against hypoxic insult, using brain slices containing the rostral striatum obtained from adult male C57/BLIcrfa(t) mice. Slices were subjected in vitro to 20 min nitrogen hypoxia, with or without addition of: (i) 50 microM haloperidol (D2 receptor antagonist and sigma ligand), (ii) 10 microM SCH23390 (selective D1 receptor antagonist), (iii) 10 microM eticlopride (selective D2 receptor antagonist), (iv) 10 microM SCH23390 and 10 microM eticlopride in combination, and (v) 10 microM MK-801 (noncompetitive NMDA receptor antagonist). Subsequently, slices were reoxygenated, fixed 2 h postinsult, and processed for light microscopy. Damage was assessed by calculating pyknotic profiles as a percentage of total neuronal profiles present. No pyknotic profiles were detected in normoxic control tissue, but this phenotype predominated in most slices subject to hypoxia alone (60.1 +/- 30.6% pyknotic profiles). Marked protection was produced by haloperidol (7.1 +/- 7.6%, P = 0.002), MK-801 (8.6 +/- 6.9%, P = 0.007), and the combined application of SCH23390 and eticlopride (5.9 +/- 9.4%, P = 0.001). No protection was demonstrated for SCH23390 or eticlopride when applied separately. These data suggest that hypoxic damage in the rostral mouse striatum is mediated via NMDA, D1, and D2 receptors. Protection against hypoxic damage by dopamine receptor antagonists requires the combined blockade of both classes of dopamine receptor.