Behavior and Cognitive Function

Fink and Swinyard, Journal of Pharmaceutical Sciences (1962),99 compared a group of pharmacological agents in an effort to detect possible tranquilizing effects. One of the tests showed that PHT markedly reduced amphetamine toxicity in aggregated mice. From their studies the authors conclude that PHT possesses tranquilizing properties and should be more fully studied in patients.

99. Fink, G. B. and Swinyard, E. A., Comparison of anticonvulsant and psychopharmacologic drugs, J. Pharm. Sci., 51: 548-551, 1962.

Tedeschi, Tedeschi, Mucha, Cook, Mattis and Fellows, Journal of Pharmacology and Experimental Therapeutics (1959),749 and Chen, Bohner and Bratton, Archives Internationates de Pharmacodynamie et de Therapie (1963),419 found that PHT suppressed fighting behavior in mice.

749. Tedeschi, R. E., Tedeschi, D. H., Mucha, A., Cook, L., Mattis, P. A., and Fellows, E. J., Effects of various centrally acting drugs on fighting behavior of mice, J. Pharmacol. and Exp. Therap. 125: 28-34, 1959.
419. Chen, G., Bohner, B., and Bratton, A. C., Jr., The influence of certain central depressants on fighting behavior of mice, Arch. Int. Pharmacodyn., 142: 30-34, 1963.

Chen and Bohner, Archives Internationales de Pharmacodynamic et de Therapie (1960),740 found, in mice, that PHT significantly inhibited scratching behavior induced by mescaline.

740. Chen, G. and Bohner, B., A study of certain CNS depressants, Arch. Int. Pharmacodyn., 125; 1-20, 1960.

Cohen and Barondes, Science (1967),59 found that PHT (35 mg/kg) significantly improved retention of learned behavior in mice given puromycin, a protein-synthesis inhibitor.

59. Cohen, H. D. and Barondes, S. H., Puromycin effect on memory may be due to occult seizures, Science, 157: 333-334, 1967.

Gordon, Recent Advances in Biological Psychiatry (1968),126 found that PHT (15-30 mg/kg) improved the deteriorated performance of older rats in both habituation and conditioned avoidance paradigms, but did not affect normal behavior in young rats. The author notes that these findings have possible application to aging in humans. He comments that the decrease in memory function and slowing of task performance in aged humans has been postulated to be caused by an abnormal prolongation of electrophysiological activity in brain, akin to static or noise, and that PHT might exert its therapeutic effects by reducing such activity.

126. Gordon, P., Diphenylhydantoin and procainamide normalization of suboptimal learning behavior, Recent Advances Biol. Psychiat., 10: 121-133, 1968.

Gordon, Callaghan and Doty, Pharmacologist (1968),1088 reported that PHT did not appear to affect the performance of normal young adult rats, but that PHT enhanced the learning level and stable memory of aged rats for avoidance paradigms. These beneficial effects were more pronounced the more difficult and novel the task. In parallel biochemical studies the authors found that PHT increased brain polyribosomal protein, rapidly-labeled RNA, and DNAase activity.

1088. Gordon, P., Callaghan, O., and Doty, B., Diphenylhydantoin effects on nucleic acid biochemistry learning and neoplasm, Pharmacologist, 10: 169, 1968.

Doty and Dalman, Psychonomic Science (1969),702 found PHT (20-60 mg/kg), thirty minutes prior to each training session, facilitated learning on discrimination and avoidance tasks. The enhancement of performance was more prominent among older rats.

702. Doty, B. and Daiman, R., Diphenylhydantoin effects on avoidance conditioning as a function of age and problem difficulty, Psychos. Sci., 14: 109-111, 1969.

Block and Moore, Personal communication,670 found that protein-deficient pigs did not perform as well as normal pigs during extinction of a conditioned avoidance response. The performance of these protein-deficient pigs was significantly improved by pretreatment with PHT.

670. Block, J. D. and Moore, A. U., Hyperresponsive extinction behavior of protein-deprived pigs reduced by diphenylhydantoin (in press).

Mouravieff-Lesuisse and Giurgea, Archives Internationates de Pharmacodynamie et de Therapie (1970),1376 found that PHT (80 mg/kg) shortened spinal fixation time in normal rats and also in those in which spinal fixation time had been prolonged by electroshock. The authors note that spinal fixation time reflects a form of memory consolidation process within spinal cord reflexes.

1376. Mouravieff-Lesuisse, F. and Giurgea, C., Influence of electro-convulsive shock on the fixation of an experience at spinal level, Arch. Int. Pharmuodyn., 183: 410-411, 1970.

Bernstein and Johnson, Bulletin of Environmental Contamination and Toxicology (1973),823 while studying the effects of PHT on estrogen metabolism in pesticide-treated quail, observed that DDT caused excitability and aggressive behavior in the quail and that PHT reduced this excitable and aggressive behavior, without any apparent sedative effect.

823. Bernstein, J. D. and Johnson, S. L., Effects of diphenylhydantoin upon estrogen metabolism by liver microsomes of DDT-treated Japanese quail, Bull. Environ. Confam. Toxicol., 10: 309-314, 1973.

Gehres, Randall, Riccio and Vardaris, Physiology and Behavior (1973),1058 found that pretreatment with PHT (20 mg/kg, subcutaneously) markedly reduced the retrograde amnesia produced by lowered body temperature in rats. In addition, electro-physiological data indicated that PHT reduced the paroxysmal electrical activity induced in the hippocampus and amygdala by the lowered body temperature.

1058. Gebres, L. D., Randall, C. L., Riccio, D. C., and Vardaris, R. M., Attenuation of hypothermic retrograde amnesia produced by pharmacologic blockage of brain seizures, Physiol. Behav., 10: 1011-1017, 1973.

Gibbs and Ng, Brain Research Bulletin (1976),1851, 2196 found that PHT (100 µM) counteracted amnesia induced by ouabain and cycloheximide in one-day-old chicks.

1851. Gibbs, M. E. and Ng, K. T., Diphenylhydantoin facilitation of labile, protein-independent memory, Brain Research Bulletin, 1: 203-8, 1976.

2196. Gibbs, M.E. and Ng, K.T., Counteractive effects of notepinephrine and amphetamine on ouabain-induced amnesia, Pharmac. Biochem. Behav., 6(5): 533-7, 1977.

File and Lister, Neuroscience Letters (1983), 2493 reported that PHT (10 mg/kg, intraperitoneally) reversed the anxiogenic effects of Ro 5-4864, a selective ligand for benzodiazepine micromolar receptors in rats.

2493. File, S. E., Lister, R. G., The anxiogenic action of Ro 5-4864 is reversed by phenytoin, Neurosci. Lett., 35: 93-6,1983.

Paule and Killam, Federation Proceedings (1984),2852 studied the effects of PHT (2.5-40 mg/kg/day, for a two-week period) on the performance of incremental repeated acquisition and incremental fixed-ratio tasks in epileptic baboons. At or below doses of PHT necessary for maximal control of induced seizures (20 mg/kg/day, achieving blood levels of 7-8 g/ml), the animals showed less variability in response rates for the most difficult tasks. The authors suggest that PHT made the baboons more attentive to the learning task and note that their results are consistent with other reports of PHT's benefits in human cognitive processes. See also Refs. 2473, 2853.

2852. Paule, M. C., Killam, E. K., The effects of chronic phenytoin administration on incremental repeated acquisition (learning) tasks in the epileptic baboon, papio papio, Fed. Proc., 43(4): 1035, 1984.
2473. Editor, Antiepileptic drug may enhance attentiveness, FASEB News, 1-2, 1984.
2853. Paule, M. C., Killam, E. K., Serum anticonvulsant levels during chronic administration in the immature epileptic baboon, Papio papio, Proc. West. Pharmacol. Soc., 38: 169-72, 1985.

Barratt, Faulk, Brandt and Bryant, Neuropsychobiology (1986),3626 used brain mapping techniques to examine the effects of PHT on the N100 sensory visual potential, as well as the late positive complex (LPC), which reflects cognitive processing. The authors emphasize that augmentation of the N100 potential is associated with impulsivity and attentional distraction. The N100 and LPC potentials were recorded from six normal subjects given the task of counting a series of bright and dim light flashes. Recordings were made before, and one hour after, the subject received either PHT (100 mg) or placebo, depending on the trial. PHT significantly reduced the intensity response of N100 at the vertex and anterior temporal sites, with a lesser reduction at the frontal pole. In addition, PHT enhanced the frontal negative portion of the slow wave LPC component, but not the positive portion of the slow wave or P300 LPC components. The authors comment that their findings are consistent with behavioral evidence that PHT reduces impulsivity and improves concentration. Plasma levels of PHT at one hour ranged from 0.6 to 0.8 g/ml, indicating that plasma levels do not always correlate with PHT's effects.

3626. Barratt, E.S., Faulk, D.M., Brandt, M.E., and Bryant, S.G., Effects of phenytoin on N100 augmenting/reducing and the late positive complex of the event-related potential: A topographic analysis, Neuropsychobiology, 15: 201-7, 1986.

See also Refs.

3627. Barratt, E.S., Shappell, S.A., and Brandt, M.E., Effects of acute phenytoin on cortical event-related potentials, Soc. Neurosci. Abstr., 14(PT 2): 1105, 1988.

3628. Barratt, E.S., Kent, T., Bryant, S., Felthous, A., and Stanford, M., Phenytoin improves brain functions among impulsive aggressive prisoners, Soc. Neurosci. Abstr.,16(PT 1): 141, 1990.

3629. Barratt, E.S., Kent, T., and Stanford, M., The effects of phenytoin on event-related potentials among impulsive aggressive prisoners, Presented at the 3rd International Brain Research Organization World Congress of Neuroscience, Montreal, Canada, 342, ABS P53.10, 1991.

3630. Barratt, E.S. and Kent, T., The effects of phenytoin (PHT) on frontal and parietal event-related potentials(ERPs) among impulsive aggressive prisoners, Presented at the XVIIIth Collegium International Neuropsychopharmacolicum Congress, Nice, France, 1992.

3631. Barratt, E.S., Stanford, M.S., Felthous, A.R., and Kent, T.A., The effects of phenytoin on impulsive and premeditated aggression: a controlled study, J. Clin. Psychopharmacology, 17(5): 341-349, 1997.

3632. Barratt E.S., Orozco-Cabal, L.F., Mishalaine, J., and Moeller, F.G., The effects of phenytoin and sodium valproate on cortical ERP's: Implications for impulsivity, Soc. Neurosci. Abstr., 2003.

Keele, NeuroReport (2001), 3633 examined the anti-aggression properties of PHT in rodent isolation-induced aggression. A resident-intruder test was used to assess the level of isolation-induced aggression in resident rats. The rats were randomly assigned to one of four treatment groups to receive either saline (SAL) or PCPA followed by either vehicle (VEH) or PHT. Animals in the PCPA group received 300 mg/kg for 3 days followed by 100mg/kg for 4 weeks. The second treatment condition consisted of daily i.p. injections of either VEH or PHT for days 28-32. Animals were tested in the resident-intruder paradigm on day 32 following three practice sessions to establish baseline fighting behavior. The anti-aggressive potential of PHT was tested in order to show the effect of treatment condition on the number of attacks elicited by the presence of an intruder in the home cage of the resident rat.

PHT treatment significantly reduced the number of attacks made by PCPA pre-treated residents compared with the PCPA/VEH-treated group. The tests demonstrated that PHT increased the attack latency in PCPA-treated animals, and that the anti-aggressive effects of PHT are specific for PCPA-treated animals since PHT had no significant effect on aggressive behavior in SAL-treated animals. Results indicated that PHT is an effective treatment for reducing aggression in animals, specifically those with chronic low levels of serotonin.

3633. Keele, N.B., Phenytoin inhibits isolation-induced aggression specifically in rats with low serotonin, Neuroreport, 12(6): 1107-1112, 2001.

See also Ref.

3634. Voigt, J.P., Morgensterne, E., Comparative effects of carbamazepine, phenytoin, diazepam and clonazepam on inhibitory avoidance learning in mice, Psychopharmacology (Berlin), 108(1-2): 131-35, 1992.

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