Psychopharmacology (1985) 86 : 27 30 Psychopharmacology 9 Springer-Verlag 1985 Dopaminomimetic action of diphenylhydantoin in rat striatum: Effect on homovanillic acid and cyclic AMP levels V. Lepore 1, N. Di Reda 2, G. Defazio 1, D. Pedone 1, A. Giovine 2, C. Lanzi 1, B. Tartaglione 1, and P. Livrea 1 1 Institute of Neurology, University of Bari, 1-70124 Bari, Italy 2 Laboratory of Neurochemistry, "Casa della Divina Provvidenza", Bisceglie, 1-70124 Bari, Italy Abstract. Diphenylhydantoin (DPH) is known to induce reversible paroxysmal dyskinesias and paranoid psychosis in humans, but its interactions with dopamine (DA) metab- olism are not clear. Single doses of DPH (60-100 mg kg 1), with serum levels over 10 gg 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) adminis- tration. 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. Concomi- tant chronic treatment with DPH and Hal counteracted the development of supersensitivity of postsynaptic DA re- ceptors 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. Key words: Diphenylhydantoin - Dyskinesias - Apomor- phine - Haloperidol - Subsensitivity - HVA Cyclic AMP Reversible paroxysmal dyskinesias (Chadwick et al. 1976; Dravet et al. 1983; Luhdorf and Lund 1977) and paranoid psychosis (Franks and Richter 1979) have been reported to be unusual side effects of diphenylhydantoin (DPH). Changes in dopaminergic transmission are believed to play a primary role in these disorders, and several reports indi- cate that DPH can affect some steps in dopamine (DA) metabolism. Increased availability of DA at receptor sites can be determined by the inhibitory effect of DPH on monoamine oxidase (MAO) (Woodbury 1980), aldehyde reductase (Turner 1979) and catechol-O-methyl-transferase (COMT), the latter probably depending on brain folate reduction (Smith and Obbens 1979). DA uptake is inhibited by DPH (Hadfield 1972) and in rat whole brain, the alpha-methyl-p- tyrosine-induced decrease in DA content is counteracted by critical DPH doses (Elliot et al. 1977). Moreover, DPH inhibition of the Ca 2 § calmodulin stimulating effect on pro- Offprint requests to. P. Livrea tein kinase may be responsible for reduced DA release from synaptic endings (De Lorenzo and Freedman 1977). In be- havioural tasks, DPH is reported to share a neuroleptic-like effect (Elliot et al. 1977). An alteration of adenylate cyclase activity by DPH has been suggested by the DPH-induced prevention of the rise in cyclic AMP following veratradine, ouabain (Ferrendelli 1980) and maximal electroshock (Johnson and Riker 1982). Moreover, cyclic AMP levels were unaffected in mouse striatum (Ferrendelli 1980), de- creased in cerebrai cortex and increased in cerebellum (Pahner et al. 1979) by DPH. This paper reports preliminary data indicating that both acute and chronic DPH treatment interfere with changes in homovanillic acid (HVA) produced by haloperidol (Hal) and apomorphine (Apo) in striatum, and that acute DPH increases cyclic AMP striatal levels. These effects suggest a dopaminomimetic DPH effect, and indicate the develop- ment of postsynaptic DA receptor subsensitivity after chronic DPH treatment. Materials and methods Animals. Male wistar rats (Nossan, Milan, Italy), weighing 220-230 g were used. The animals were housed in groups of five in standard cages; they were given free access to food (Nossan, Milan, Italy) and water, and exposed to a constant room temperature (20-22 ~ C) in a light cycle of 14 h/day (light from 6 a.m. to 8 p.m.). All animals were allowed to acclimate to the laboratory environment for 48 h before experiments. Drugs. Treatments were performed with DPH (sodium salt, Recordati, Milan, Italy, 50 mg ml 1 0.1 M NaOH) (Palmer et al. 1979), Hal (haloperidol, Lusofarmaco, Milan, Italy, Img ml-1 sterile distilled water), Apo (apomorphine hy- drochloride, Sigma, St. Louis, USA, 1 mg ml ~ sterile dis- tilled water). Treatment schedules are reported in the figure and table legends. Peak serum levels of DPH were found 2 h after IP administration; mean (• SE) serum levels were: 8.7_+2 gg ml -~ after 30mg kg-1; 21_+4 lag m1-1 after 60rag kg 1; 34_+8 lagml 1 after 100 mg kg -1. Neither concomitant acute treatment with Hal and Apo nor previous chronic Hal treatment affected serum levels of DPH achieved after a single dose. DPH was undetectable in serum 48 h after cessation of subchronic and chronic treatment. Acute and chronic treatment with DPH alkaline vehicle affected neither locomotor activity nor health of