Diphenylhydantoin (DPH) is known to induce reversible paroxysmal dyskinesias and paranoid psychosis in humans, but its interactions with dopamine (DA) metabolism are not clear. Single doses of DPH (60-100 mg kg-1), with serum levels over 10 micrograms ml-1, reduced homovanillic acid (HVA) levels in rat striatum. The DPH-induced HVA decrease was enhanced by supersensitivity of postsynaptic DA receptors following chronic haloperidol (Hal) administration. DPH 60 mg kg-1 given acutely enhanced the HVA decrease induced by apomorphine (Apo) and partially counteracted the HVA increase following acute Hal (0.1-0.5-2 mg kg-1). After chronic DPH treatment, Apo was ineffective in reducing striatal HVA levels. Concomitant chronic treatment with DPH and Hal counteracted the development of supersensitivity of postsynaptic DA receptors to Apo. Single doses of DPH (30-60-100 mg kg-1) increased cyclic AMP striatal content; this effect was blocked by Hal. A dopaminomimetic DPH action and a subsensitivity of postsynaptic DA receptors after chronic DPH seem to be suggested. These effects could be related to the dyskinetic and psychotic syndromes produced by the drug.