, Volume 57, Issue 2, pp 137–144 | Cite as

Experimental barbiturate dependence

I. Barbiturate dependence development in rats by drug-admixed food (DAF) method
  • Eijiro Tagashira
  • Tomoko Izumi
  • Saizo Yanaura
Original Investigations


A method for testing a rat's physical-dependence liability to sedaditive-hypnotic agents and for evaluating that dependence was studied by using the method. Rats received phenobarbital- or barbital-admixed food on a graded-increase dosage schedule over 30–40 days. Manifestations of CNS-suppressing action of either drug (e.g., systemic muscle relaxation, motor incoordination, staggering gait, and ptosis) persisted day and night during the drug medication. Twenty-four to 48 h after withdrawal of either drug, abstinence symptoms (e.g., muscle fasciculation, nuchal twitching, vocalization, increased irritability, ataxia, hyperthermia, and clonic-tonic and grand mal-type convulsions) were evidenced in all animals (N=6), some of which died after convulsions. These withdrawal signs in rats were classified and found to be closely correlated with the magnitude of weight loss during the withdrawal. The classification provides a basis for quantitatively assessing physical-dependence liability. The data obtained in the present study suggest that rats, like dogs and monkeys, are suitable experimental animals for tests in early stages of dependence liability, and that the administration of drug-admixed food is a useful method of developing dependence on both barbiturate and morphine-type drugs.

Key words

Barbiturate dependence Rats Drug-admixed food Withdrawal signs of barbiturates 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Crossland, J., Leonard, B. E.: Barbiturate withdrawal convulsions in the rat. Biochem. Pharmacol. [Suppl.] 12, 103 (1963)Google Scholar
  2. Dunham, N. W., Miya, T. S.: A note on a simple apparatus for detecting neurological deficit in rats and mice. J. Am. Pharm. Assoc. 46, 208–209 (1957)Google Scholar
  3. Essig, C. F.: Barbiturate withdrawal convulsions in decrebellate dogs. Int. J. Neuropharmacol. 3, 453–456 (1964)Google Scholar
  4. Essig, C. F.: Barbiturate withdrawal in white rats. Int. J. Neuropharmacol. 5, 103–107 (1966)Google Scholar
  5. Essig, C. F.: Drug dependence: barbiturate dependence. In: Advances in mental science II. R. T. Harris, W. M. McIsaac, and C. R. Schuster, eds., pp. 129–140. Austin and London: University of Texas 1970Google Scholar
  6. Fraser, H. F., Isbell, H.: Abstinence syndromes in dogs after chronic barbiturate medication. J. Pharmacol. Exp. Ther. 112, 261–267 (1954)Google Scholar
  7. Ho, I. K.: Systematic assessment of tolerance to pentobarbital by pellent implantation. J. Pharmacol. Exp. Ther. 197, 479–487 (1976)Google Scholar
  8. Hollister, L. E., Motzenbecker, F. P., Degan, R. O.: Withdrawal reactions from chlordiazepoxide (“Librium”). Psychopharmacologia (Berl.) 2, 63–68 (1961)Google Scholar
  9. Jones, B. E., Prada, J. A., Martin, W. R.: A method for bioassay of physical dependence on sedative drugs in dog. Psychopharmacology 47, 7–15 (1976)Google Scholar
  10. Kaneto, H., Koida, M., Tsuchie, F., Miyagawa, H.: A screening procedure for barbital type physical dependence liability of psychotrophic drugs. Folia Pharmacol. Jpn. 69, 729–738 (1973)Google Scholar
  11. Norton, P. R. E.: The effects of drugs on barbiturate withdrawal convulsions in the rat. J. Pharm. Pharmacol. 22, 763–766 (1970)Google Scholar
  12. Schmidt, H., Kleinman, K. M.: Effect of chronic administration and withdrawal of barbiturates upon drinking in the rat. Arch. Int. Pharmacodyn. 151, 142–149 (1964)Google Scholar
  13. Seevers, M. H., Tatum, A. L.: Chronic experimental barbital poisoning. J. Pharmacol. Exp. Ther. 42, 217–231 (1931)Google Scholar
  14. Stanton, E. J.: Addiction and tolerance to barbiturates? The effects of daily administration and abrupt withdrawal of phenobarbital-sodium and pentobarbital-sodium in the albino rat. J. Pharmacol. Exp. Ther. 57, 245–252 (1936)Google Scholar
  15. Tagashira, E., Izumi, T., Yanaura, S.: Studies on drug dependence: tolerance to and dependence on barbiturates by drug-admixed food ingestion. Folia Pharmacol. Jpn. 72, 34 (1976a)Google Scholar
  16. World Health Organization [WHO] Technical Report, Series No. 287: Evaluation of dependence-producing drugs (1964)Google Scholar
  17. World Health Organization Technical Report, Series No. 557: Evaluation of dependence liability and dependence potential of drugs (1975)Google Scholar
  18. Yanagita, T., Takahashi, S.: Development of tolerance to and physical dependence on barbiturates in rhesus monkeys. J. Pharmacol. Exp. Ther. 172, 163–169 (1970)Google Scholar
  19. Yanagita, T., Takahashi, S.: Dependence liability of several sedative-hypnotic agents evaluated in monkeys. J. Pharmacol. Exp. Ther. 185, 307–316 (1973)Google Scholar
  20. Yanaura, S., Tagashira, E.: Comparison of drug dependence formation in naive and drug dependence-experienced rats. Folia Pharmacol. Jpn. 71, 157–168 (1975a)Google Scholar
  21. Yanaura, S., Tagashira, E., Suzuki, T.: Physical dependence on morphine, phenobarbital and diazepam in rats by drug-admixed food ingestion. Jpn. J. Pharmacol. 25, 453–463 (1975b)Google Scholar
  22. Yanaura, S., Tagashira, E., Izumi, T.: Studies on dependence of short acting drugs in rats. Folia Pharmacol. Jpn. 71, 329–337 (1975c)Google Scholar

Copyright information

© Springer-Verlag 1978

Authors and Affiliations

  • Eijiro Tagashira
    • 1
  • Tomoko Izumi
    • 1
  • Saizo Yanaura
    • 1
  1. 1.Department of PharmacologyHoshi College of PharmacyTokyoJapan

Personalised recommendations