Abstract
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 μg 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.
Similar content being viewed by others
References
Carenzi A, Cheney DL, Costa E, Guidotti A, Racagni G (1975) Action of opiate, antipsychotics, amphetamine and apomorphine on dopamine receptors in rat striatum: in vivo changes of 3′, 5′-cyclic AMP content and acetylcholine turnover rate. Neuropharmacology 14:927–939
Chadwick D, Reynolds EH, Marsden CD (1976) Anticonvulsant-induced dyskinesias: a comparison with dyskinesias induced by neuroleptics. J Neurol Neurosurg Psychiatr 39:1210–1218
Clement-Cormier YC, Kebabian JW, Petzold GL, Greengard P (1974) Dopamine sensitive adenylate cyclase in mammalian brain: a possible site of action of anticonvulsant drugs. Proc Natl Acad Sci USA 71:1113–1117
Costa E (1980) Receptor plasticity: Biochemical correlates and pharmacological significance. In: Cattabeni F, Racagni G, Spano PF, Costa E (eds) Long term effects of neuroleptics. Raven Press, New York, pp 363–377
De Lorenzo RJ, Freedman SD (1977) Possible role of calcium dependent protein phosphorylation in mediating neurotransmitter release and anticonvulsant action. Epilepsia 18:357–365
Dravet C, Dalla Bernardina B, Mesdjian E, Galland MC, Roger J (1983) Phenytoin-induced paroxysmal dyskinesia. In: Oxley J, Janz D, Meinardi H (eds) Antiepileptic therapy: chronic toxicity of antiepileptic drugs. Raven Press, New York, pp 229–235
Elliot PN, Jenner P, Chadwick D, Reynolds E, Marsden CD (1977) The effect of diphenylhydantoin on central catecholamine containing neuronal system. J Pharm Pharmacol 29:41–43
Ferrendelli JA (1980) Phenytoin: cyclic nucleotide regulation in the brain. In: Glaser GH, Penry JK, Woodbury DM (eds) Antiepileptic drugs: mechanisms of action Raven Press, New York, pp 429–433
Franks RD, Richter AJ (1979) Schizofrenia-like psychosis associated with anticonvulsant toxicity. Am J Psychiatry 136:973–974
Glowinsky J, Iversen L (1966) Regional studies of catecholamine in the rat brain. J Neurochem 13:655–699
Gnegy M, Treisman G (1981) Interaction of calmodulin and guanyl nucleotides in the stimulation of rat striatal adenylate cyclase activity. In: Gessa GL, Corsini GU (eds) Apomorphine and other dopaminomimetics. Raven Press, New York, pp 161–170
Hadfield GH (1972) Uptake and binding of catecholamines. Effect of diphenylhydantoin and a new mechanism of action. Arch Neurol 26:78–84
Hanbauer I, Gimble J, Lovenberg W (1979) Changes in soluble calmodulin following activation of dopamine receptors in rat striatal slices. Neuropharmacology 18:851–857
Hanbauer I, Memo M (1981) Long term modulation of dopamine receptor sensitivity: participation of calmodulin. In: Gessa GL, Corsini GU (eds) Apomorphine and other dopaminomimetics. Raven Press, New York, pp 171–178
Johnson SW, Riker WK (1982) Phenytoin antagonism of electrically induced maximal seizures in frogs and mice and effects on central nervous system levels of adenosine 3′, 5′-monophosphate and guanosine 3′, 5′-monophosphate. J Pharmacol Exp Ther 221:139–145
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275
Luhdorf K, Lund M (1977) Phenytoin-induced hyperkinesia. Epilepsia 18:409–415
Mendez JS, Cotzias GC, Mena I, Papavasiliou PS (1975) Diphenylhydantoin: blocking of l-dopa effects. Arch Neurol 32:44–46
Middaugh LD, Grover TA, Zemp JW (1979) Effects of dietary folic acid reduction on tissue folate concentrations and on neurochemical and behavioural aspects of brain function in adult and developing mice. In: Botez MI, Reynolds EH (eds) Folic acid in neurology, psychiatry and internal medicine. Raven Press, New York, pp 213–228
Palmer GC, Jones DJ, Medina MA, Stavinoha WB (1979) Anticonvulsant drug actions on in vitro and in vivo levels of cyclic AMP in the mouse brain. Epilepsia 20:95–104
Roos BE (1969) Decrease in homovanillic acid as evidence for dopamine receptor stimulation by apomorphine in the neostriatum of the rat. J Pharm Pharmacol 21:263–264
Shah DS, Chambon P, Guidotti A (1981) Binding of (3H)-5,5diphenylhydantoin to rat brain membranes. Neuropharmacology 20:1115–1119
Smith DB, Obbens EA (1979) Antifolate-antiepileptic relationship. In: Botez MI, Reynolds EH (eds) Folic acid in neurology, psychiatry and internal medicine. Raven Press, New York, pp 267–283
Turner AJ (1979) The relationship between brain folate and monoamine metabolism. In: Botez MI, Reynolds EH (eds) Folic acid in neurology, psychiatry and internal medicine. Raven Press, pp 165–167
Uzonov P, Gnegy ME, Revuelta A, Costa E (1976) Regulation of the high Km cyclic nucleotide phosphodiesterase of adrenal medulla by the endogenous calcium-dependent protein activator. Biochem Biophys Res Commun 70:132–138
Westerink BC (1978) Effect of centrally acting drugs on regional dopamine metabolism. In: Roberts PJ, Woodruff GH, Iversen LL (eds) Advances in Biochemical Psychopharmacology vol. 19, Raven Press, New York, pp 255–266
Westerink BC, Korf J (1975) Determination of nanogram amounts of HVA in the CNS with a rapid semiautomated method. Biochem Med 12:106–115
Woodbury DM (1982) Phenytoin: mechanism of action. In: Woodbury DM, Penry JK, Pippinger CE (eds) Antiepileptic drugs. Raven Press, New York, pp 269–281
Woodbury DM (1980) Phenytoin: proposed mechanism of anticonvulsant action. In: Glaser GH, Penry JK, Woodbury DM (eds) Antiepileptic drugs: mechanism of action. Raven Press, New York, pp 447–471
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lepore, V., Di Reda, N., Defazio, G. et al. Dopaminomimetic action of diphenylhydantoin in rat striatum: Effect on homovanillic acid and cyclic AMP levels. Psychopharmacology 86, 27–30 (1985). https://doi.org/10.1007/BF00431679
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00431679