Synaptosomal membrane Na+, K+-ATPase is inhibited by neurotensin, an effect which involves its high affinity receptor (NTS1) [Lopez Ordieres MG, Rodriguez de Lores Arnaiz, G. Peptides 2000; 21:571-576.]. Herein, the effect of neurotensin on synaptosomal membrane Na+, K+-ATPase of rats 18 h after i.p. administration of antipsychotic haloperidol (2 mg/kg) or clozapine (10 mg/kg) was studied. Basal enzyme activity after these treatments did not differ from that in vehicle-treated rats. It was observed that 3.5 x 10(-6) M neurotensin reduced roughly 40% cerebral cortex Na+, K+-ATPase from vehicle-injected rats, produced no effect on the enzyme from rats injected with haloperidol but enhanced 26% that from rats injected with clozapine. The peptide decreased 40% striatal Na+, K+-ATPase from vehicle-injected rats or from rats injected with clozapine, whereas it failed to alter this enzyme activity from rats injected with haloperidol. Haloperidol and clozapine (1 x 10(-6) M) added in vitro failed to alter Na+, K+-ATPase activity in cerebral cortex synaptosomal membranes. Results obtained after antipsychotic administration may well offer an alternative explanation for the particular side effects recorded in therapeutics by typical (haloperidol) versus atypical (clozapine) antipsychotic drugs.