Changes in seizure threshold and aggression during chronic treatment with three anticonvulsants and on drug withdrawal

Abstract

Sodium phenobarbitone (20 and 70 mg/kg) had a significant anticonvulsant action against pentylenetetrazole-induced seizures, which persisted for 21 days of treatment. On drug withdrawal there was a significant decrease in seizure threshold below control level 24–48 h after the last dose of 70 mg/kg. Phenytoin (40 mg/kg) had a significant anticonvulsant action after 7 days of treatment and this persisted for 21 days of treatment. On drug withdrawal there was a significant decrease in seizure threshold 48 h after the last dose. Lorazepam (0.1 mg/kg) had a significant anticonvulsant action, but the group tested after 21 days of treatment did not differ from the controls, indicating that tolerance had developed to this effect; on drug withdrawal there was a decrease in seizure threshold from 24 to 72 h. The only drug to increase aggressive behaviour was sodium phenobarbitone (70 mg/kg); this reached significance after 14 and 21 days of treatment and occurred 8 h after drug administration; 0.5 h after drug administration phenobarbitone (70 mg/kg) abolished aggressive behaviour. After 7 days of treatment phenobarbitone (70 mg/kg) increased social behaviour 0.5 h after administration and this was still increased after 21 days of treatment. On drug withdrawal, there were no changes in aggressive behaviour, but there were significant decreases in social behaviour 24 and 48 h after phenobarbitone (70 mg/kg) withdrawal and 24, 48 and 72 h after lorazepam (0.1 mg/kg) withdrawal.

This is a preview of subscription content, access via your institution.

References

  1. Browne TR (1976) Clonazepam. A review of a new anticonvulsant drug. Arch Neurol 33:326–332

    PubMed  Google Scholar 

  2. Dingemanse J, van Bree JBMM, Danhof M (1988a) Pharmacokinetic modelling of the anticonvulsant response of phenobarbital in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure. In: Dingemanse J (ed) Pharmacokinetic-pharmacodynamic modelling of drug effects on the central nervous system, Drukkerij J.H. Pasmans, Gravenhage, pp 172–188

    Google Scholar 

  3. Dingemanse J, Sollie FAE, Breimer DD, Danhof M (1988b) Pharmacokinetic modelling of the anticonvulsant response of oxazepam in rats using the pentylenetetrazol threshold concentration as pharmacodynamic measure. J Pharmacokinet Biopharm 16:203–213

    Article  PubMed  Google Scholar 

  4. File SE (1985) Tolerance to the behavioural actions of benzodiazepines. Neurosci Biobehav Rev 9:113–122

    Article  PubMed  Google Scholar 

  5. File SE, Baldwin HA (1989) Changes in anxiety in rats tolerant to, and withdrawn from, benzodiazepines: behavioural and biochemical studies. In: Tyrer P (ed) Psychopharmacology of anxiety, Oxford University Press, Oxford, pp 28–51

    Google Scholar 

  6. File SE, Pellow S, Wilks LJ (1985) Anticonvulsant effects of chronic treatment with phenytoin against pentylenetetrazole-induced seizures in the mouse. Neuropharmacology 24:969–973

    Article  PubMed  Google Scholar 

  7. File SE, Wilks LJ, Mabbutt PS (1989a) The role of the benzodiazepine receptor in mediating long-lasting anticonvulsant effects and the late-appearing reductions in motor activity and exploration. Psychopharmacology 97:349–354

    Article  PubMed  Google Scholar 

  8. File SE, Wilks LJ, Mabbutt PS (1989b) Withdrawal, tolerance and sensitization after a single dose of lorazepam. Pharmacol Biochem Behav 31:937–940

    Article  Google Scholar 

  9. Frey HH (1986) Experimental evidence for the development of tolerance to anticonvulsant drug effects. In: Frey HH, Froscher W, Koella WP, Meinardi H (eds) Tolerance to beneficial and adverse effects of antiepileptic drugs. Raven Press, New York, pp 7–16

    Google Scholar 

  10. Froscher W, Engels HG (1986) Tolerance to the anticonvulsant effect of clonazepam. In: Frey HH, Froscher W, Koello WP, Meinardi H (eds) Tolerance to beneficial and adverse effects of antiepileptic drugs. Raven Press, New York, pp 127–136

    Google Scholar 

  11. Goodman LS, Swinyard EA, Brown WC, Schiffman DO, Grewal MS, Bliss EL (1953) Anticonvulsant properties of 5-phenyl-5-ethyl-hexahydropyridimidine-4,6-dione (Mysoline) a new antiepileptic. J Pharmacol Exp Ther 108:428–436

    PubMed  Google Scholar 

  12. Kalant H, LeBlanc AE, Gibbins RJ (1971) Tolerance to, and dependence on, some non-opiate psychotropic drugs. Pharmacol Rev 23:135–191

    PubMed  Google Scholar 

  13. Lader MH, File SE (1987) The biological basis of benzodiazepine dependense. Psychol Med 17:539–547

    PubMed  Google Scholar 

  14. Lister RG, Abernethy DR, Greenblatt DJ, File SE (1983) Methods for the determination of lorazepam and chlordiazepoxide and metabolites in brain tissue. J Chromatogr Biomed Appl 277:201–208

    Article  Google Scholar 

  15. Nutt DJ, Taylor SC, Little HJ (1986) Optimising the pentetrazol infusion test for seizure threshold measurement. J Pharm Pharmacol 38:697–698

    PubMed  Google Scholar 

  16. Oxley J (1986) Tolerance to the antiepileptic effect of clobazam in patients with severe epilepsy. In: Frey HH, Froscher W, Koella WP, Meinardi H (eds) Tolerance to beneficial and adverse effects of antiepileptic drugs. Raven Press, New York, pp 119–126

    Google Scholar 

  17. Robertson MM (1986) Current status of the 1,4- and 1,5-benzodiazepines in the treatment of epilepsy: the place of clobazam. Epilepsia 27:S27-S41

    Google Scholar 

  18. Schmidt D, Rhode M, Wolf P, Roeder-Wanner U (1986) Tolerance to the antiepileptic effect of clobazam. In: Frey HH, Froscher W, Koella WP, Meinardi H (eds) Tolerance to beneficial and adverse effects of antiepileptic drugs. Raven Press, New York, pp 109–118

    Google Scholar 

  19. Swinyard EA, Brown WC, Goodman L (1952) Comparative assays of antiepileptic drugs in mice and rats. J Pharmacol Exp Ther 106:319–330

    PubMed  Google Scholar 

  20. Wilks LH, File SE (1988) Evidence for simultaneous anxiolytic and aversive effects several hours after administration of sodium phenobarbitone to the rat. Neuropsychobiology 19:86–89

    PubMed  Google Scholar 

  21. Wilks LJ, File SE, Dingemanse J (1988) Hyperactivity and increased aggression in the rat several hours after a single dose of phenobarbital. Pharmacopsychoecologia 1:23–31

    Google Scholar 

  22. Wolf SM, Forsythe A (1978) Behavior disturbance, phenobarbital and febrile seizures. Pediatrics 61:728–731

    PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Sandra E. File.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

File, S.E., Wilks, L.J. Changes in seizure threshold and aggression during chronic treatment with three anticonvulsants and on drug withdrawal. Psychopharmacology 100, 237–242 (1990). https://doi.org/10.1007/BF02244413

Download citation

Key words

  • Barbiturate
  • Diphenylhydantoin
  • Benzodiazepine
  • Anticonvulsant
  • Aggression
  • Social behaviour
  • Tolerance
  • Withdrawal