The interactions between dizocipline, an N-methyl-D-aspartate open channel antagonist, and the induction of water drinking and c-fos expression by intracerebroventricular (i.c.v.) infusion of angiotensin II have been studied. Pretreating male rats with i.c.v. dizocilpine maleate (100 or 300 nmol) or tenocyclidine (150 nmol), both non-competitive N-methyl-D-aspartate antagonists, inhibited the subsequent dipsogenic response to i.c.v. angiotensin II (125 or 50 pmol, 5-10 min later). Dizocilpine also decreased the angiotensin II-evoked expression of c-fos in the median preoptic nucleus, supraoptic nucleus and the medial (parvicellular) and lateral (magnocellular) parts of the hypothalamic paraventricular nucleus, as well as in the nucleus of the solitary tract and the lateral parabrachial nucleus. Double staining showed that suppression of c-fos expression occurred in N-methyl-D-aspartate R1 receptor containing neurons in the hypothalamus. Pretreating rats with any of three competitive glutamate antagonists (2-amino-5-phosphonopentanoic acid, 60 or 160 nmol; gamma-D-glutamylglyine, 400 nmol; (DL-3/(R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, 0.1 nmol) or the glycine site antagonist 7-chlorokynurenic acid had no effects on angiotensin II-induced drinking. Neither did pretreating rats with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist 6-cyano-7-nitroquinoxaline-2,3-dione [two infusions, 30 min (240 nmol) and 5 min (160 nmol) before angiotensin II]. To eliminate cross-reactivity of dizocilpine with nicotinic receptors, animals were pretreated with nicotinic acetylcholine blocker mecamylamine (250 nmol, i.c.v.), but this had no effect on angiotensin II-dependent drinking or c-fos expression. These results suggest that an N-methyl-D-aspartate-type glutamate receptor is implicated in the dipsogenic and cellular responses to i.c.v. angiotensin II, and point to the existence of a novel set of interactions between excitatory amino acids and this neuropeptide.