Hadfield and Boykin, Research Communication on Chemistry, Pathology and Pharmacology (1974),¹¹⁰⁸ studied the effect of PHT, administered orally and intraperitoneally for fourteen days, on [³H]-norepinephrine uptake by isolated rat brain synaptosomes. The authors observed that PHT stimulated the uptake of norepinephrine when the medium was anoxic. They note that these in vivo results are confirmatory of their earlier in vitro results in which PHT was added directly to the isolated synaptosomes.¹¹⁰⁹ The authors conclude that this provides further evidence for the regulatory effect of PHT on uptake, storage and release of neurotransmitters in brain.

1108. Hadfield, M. G. and Boykin, M. E., Effect of diphenylhydantoin administered in vivo on 3H-1-norepinephrine uptake in synaptosomes, Res. Commun. Chem. Pathol. Pharmacol., 7: 209-212, 1974.
1109. Hadfield, M. G.,Uptake and binding of catecholamines -effect of diphenylhydantoin and a new mechanism of action, Arch. Neurol., 26: 78-84, 1972.

Lew, Proceedings of the Society of Experimental Biology and Medicine (1975),¹²⁸² found that PHT increased the concentration of norepinephrine in the hypothalamus, cerebellum and brainstem in a strain of naturally hypertensive rats. The author notes that a deficiency of norepinephrine in the hypothalamus has been reported with hypertension.

1282. Lew, G. M., Increased hypothalamic norepinephrine in genetically hypertensive rats following administration of diphenylhydantoin, Proc. Soc. Exp. Biol. Med., 148: 30-32, 1975.

Hadfield and Weber, Biochemical Pharmacology (1975),¹⁸⁷⁵ in a study of fighting mice and non-fighting mice, found that the uptake of [³H]-norepinephrine was increased by fighting. PHT (100 µM) significantly decreased this uptake. The authors state that inhibition of norepinephrine up-take may explain PHT's effect on aggressive behavior in animals and humans.

1875. Hadfield, M. G. and Weber, N. E., Effect of fighting and diphenylhydantoin on the uptake of 3H-1-norepinephrine in vitro in synaptosomes isolated from retired male breeding mice. Biochem. Pharmacol., 24: 1538-40, 1975.

Hadfield and Rigby, Biochemical Pharmacology (1976),¹⁸⁷⁴ measured [³H]-dopamine uptake in striatal synaptosomes from fighting mice. They found that intense fighting produced virtually instantaneous increases in dopamine uptake and that PHT (100 µM) inhibited this uptake.

1874. Hadfield, M. G. and Rigby, W. F. C., Dopamine: Adaptive uptake changes in striatal synaptosomes after 30 seconds of intense fighting, Biochem. Pharmacol., 25: 2752-4, 1976.

Fry and Ciarlone, Neuropharmacology (1981),²¹⁹¹ studied cerebellar levels of serotonin and norepinephrine, two to twenty-eight hours after a single intraperitoneal PHT injection in mice. PHT (20 mg/kg) increased levels of both norepinephrine and serotonin by up to 22%, with increases observed as early as four hours. Elevated levels were also seen at twenty-eight hours. The authors suggest that the PHT may in part regulate hyperexcitability in the nervous system by increasing the levels of these inhibitory neurotransmitters in the cerebellum, thereby enhancing the effects of cerebellar inhibition on other brain regions. (See also Ref. 1839.)

2191. Fry, B.W. and Ciarione, A.E., Effects of phenytoin on mouse cerebellar 5-hydroxytryptamine and norepinephrine, Neuropharmacology 20: 623-5, 1981.
1839. Fry, B. and Ciarlone, A. E., Phenytoin increases norepinephrine (NE) and serotonin (5-HT) in mouse cerebellum, Pharmacologist, 21(3): 183, 1979.

Quattrone, Crunelli and Samanin, Neuropharmacology (1978),²⁸⁸⁶ evaluated the possible involvement of neurotransmitters in the control of hyperexcitability in the rat central nervous system by PHT, phenobarbital and carbamazepine. Brain levels of norepinephrine and serotonin were selectively lowered, using 6-hydroxydopamine and raphe lesions, respectively, prior to measuring seizure threshold and PHT's antiseizure effects. The authors found that lowered norepinephrine levels reduced seizure threshold and lessened PHT's effects. PHT's antiseizure actions, however, were less affected than those of phenobarbital and carbama-zepine. Raphe lesions, which were used to lower brain serotonin levels, did not change seizure threshold or alter the effectiveness of any of the drugs.

2886. Quattrone, A., Crunelli, V., Samanin, R., Seizure susceptibility and anticonvulsant activity of carbamazepine, diphenylhydantoin and phenobarbital in rats with selective depletions of brain monoamines, Neuropharmacology, 17: 643-7, 1978.

De Boer, Stoff and Van Duijn, Brain Research (1982),²⁴³⁶ reported the effects of PHT and other drugs on potassium-induced presynaptic release of norepinephrine, serotonin, acetylcholine, GABA and glutamate in rat cortical slices. PHT reduced the release of norepinephrine and serotonin at concentrations as low as 8-20 µM. GABA and glutamate release was affected only at higher concentrations of PHT (100-200 µM). Acetylcholine release was not affected by doses up to 200 µM in these experiments. While diazepam and sodium valproate had little effect on neurotransmitter release, phenobarbital and pentobarbital, especially at high concentrations, reduced release of all neurotransmitters. At concentrations which cause neuronal hyperexcitability, penicillin and pentylenetetrazol increased release of the excitatory neurotransmitter glutamate. The authors suggest that PHT's ability to regulate neurotransmitter release is important in its effects on hyperexcitability and stress that these effects may be more prominent in abnormal membrane states.

2436. De Boer, T., Stoof, J. C., Van Duijn, H., The effects of convulsant and anticonvulsant drugs on the release of radiolabeled GABA, glutamate, noradrenaline, sertonin and acetylcholine from rat cortical slices, Brain Res., 253: 153-60, 1982.

Matsumoto, Hiramatsu and Mori, IRCS Medical Science (1983),²⁷⁷¹ evaluated the effects of PHT (40 mg/kg intraperitoneally for three days) on serotonin levels in the forebrain and cerebellum of mice with a hereditary susceptibility to seizures. PHT increased the levels of serotonin at both sites and completely prevented stimulation-provoked seizures.

2771. Matsumoto, Y., Hiramatsu, M., Mori, A., Effects of phenytoin on convulsions and brain 5-hydroxytryptamine levels in E1 mice, IRCS Med. Sci. Biochem., 11(9): 837, 1983.

Matsumoto, Hiramatsu and Mori, Neurosciences (1984),²⁷⁷² evaluated the effects of fourteen-day treatment of mice with intraperitoneal PHT (40 mg/kg) on brain norepinephrine, dopamine, and serotonin. Levels of norepinephrine and dopamine in the cerebrum increased from the first day, attaining a maximum on the fifth and sixth day (20-40% higher) and then decreased to above-baseline levels, which were constant from the seventh to the fourteenth day. The serotonin levels attained a maximum on the fourth day (30% above normal) and then decreased to constant above-baseline levels from the fifth to the fourteenth day. Levels of norepinephrine and dopamine in the cerebellum attained a maximum on the third day.

2772. Matsumoto, Y., Hiramatsu, M., Mori, A., Effects of chronic administration of phenytoin on its metabolism and brain monoamine level, Neurosciences (Kobe, Jpn), 10: 183-9, 1984.

Pratt, Jenner and Marsden, Neuropharmacology (1985),²⁸⁸¹ found that PHT (40 mg/kg and above, 1.5 hours prior to measurements) caused a dose-related elevation of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan in mouse brain. Their studies indicated that PHT did not affect synthesis, but rather decreased utilization of serotonin.

Diamond and Nguyen, Neurology (1988),³⁴⁹⁷ reported that MPTP (30 mg/kg s.c.) administered to mice reduced their locomotor activity and produced a 35% reduction in striatal dopamine. Chronic PHT (50 mg/kg) given for seven days prevented the decrease in dopamine. The authors comment that their results suggest that PHT retards the development of MPTP-induced Parkinson's disease.

3497. Diamond, B.I. and Nguyen, T.H., Effect of seizures and diphenylhydantoin on MPTP toxicity, Neurology, 38(SUP 1): 332, 1988.

Markianos and Kalfakis, Functional Neurology (1991),³⁴⁹⁸ measured the serotonin, dopamine, and noradrenaline metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and methoxyhydroxyphenylglycol (MHPG), in urine of 38 male patients with idiopathic epilepsy on a single drug regime, and in 36 healthy males controls. Twenty patients were on carbamazepine and 18 on phenytoin. The concentrations of HVA and MHPG did not differ from normal, but 5-HIAA was significantly reduced in both patient and groups. The authors interpret their finding of reduced serotonin catabolism in their treated patients as an action of phenytoin or carbamazepine that increases brain serotonin levels by protecting its breakdown, resulting in a better utilization of the neurotransmitter in the synapses.

3498. Markianos, M. and Kalfakis, N., Neurotransmitter metabolites in medicated epileptic patients, Funct. Neurol., 6(4): 367-370, 1991.

See also Refs. 1789, 2086, 2329, 2554, 2624, 2685, 2703.

2881. Pratt, J. A., Jenner, P., Marsden, C. D., Comparison of the effects of benzodiazepines and other anticonvulsant drugs on synthesis and utilization of 5-HT in mouse brain, Neuropharmacology, 24(l): 59-68, 1985.
1789. Dadkar, M. K., Gupte, R. D. and Dohadwalia, A. M., Effect of diphenylhydantoin on blood pressure of spontaneously hypertensive rats, Med. Biol., 57: 398-401, 1979.
2086. Snider, S. R. and Snider, R. S., Phenytoin and cerebellar lesions: similar effects on cerebellar catecholamine metabolism, Arch. Neurol., 34: 162-7, 1977.
2329. Bhattacharya, S. K., Bhattacharya, D., Effect of restraint stress on anticonvulsant actions of phenobarbitone and diphenylhydantoin in rats, Indian J. Exp. Biol., 20: 406-8, 1982.
2554. Green, A. R., Grahame-Smith, D. G., The effect of diphenylhydantoin on brain 5-hydroxytryptamine metabolism and function, Neuropharmacology, 14: 107-13, 1975.
2624. Jenner, P., Marsden, D., Pratt, J., Actions of benzodiazepines and other anticonvulsants on 5HT turnover in mouse brain, Br. J. Pharynacol., 74: 812-3p, 1981.
2685. Lalonde, R., Botez, M. I., Chronic phenytoin and the stereotyped motor response induced by 5-methoxy-N, N-dimethyltryptamine in rats, Brain Res., 326: 388-91, 1985.
2703. Lepore, V., Di Reda, N., Defazio, C., Pedone, D., Giovine, A., Lanzi, C., Tartaglione, B., Livrea, P., Dopaminomimetic action of diphenylhydantoin in rat striatum: effect on homovanillic acid and cyclic AMP levels, Psychopharmacology, 86: 27-30, 1985.