Advertisement

Benzodiazepine Receptor-Mediated “Anxiety” in Primates

  • P. Skolnick
  • P. Ninan
  • T. Insel
  • J. Crawley
  • S. Paul

Abstract

During the past seven years, numerous investigations have demonstrated that the benzodiazepine receptor [in concert with an associated recognition site for GABA and a chloride ionophore] is involved in the antianxiety (anxiolytic) actions of a number of chemically unrelated substances such as the benzodiazepines, barbiturates, triazolopyridazines (e.g. CL 218,872), pyrazolopyridines (e.g. SQ 65,396), and ethanol (Skolnick and Paul, 1981). During the past three years, several compounds have been described which bind to benzodiazepine receptors with high affinities, and antagonize one or more of the pharmacologic actions of the benzodiazepines (Skolnick et al., 1982). The first of these benzodiazepine antagonists described was the ethyl ester of beta carboline-3-carboxylic acid (Tenen and Hirsch, 1980; Oakley and Jones, 1980). Although this compound was first postulated to be an endogenous ligand of the benzodiazepine receptor (Braestrup, et al., 1980), it is likely that this compound as well as the related beta carbolines extracted from human urine were formed during the isolation procedure employed (Squires, 1981). Nonetheless, these compounds have proven invaluable in both better defining the physiologic role(s) of the benzodiazepine receptor complex and providing a robust, chemically induced model of anxiety in primates.

Keywords

Ethyl Ester Acid Ethyl Ester Intrinsic Action Beta Endorphin Convulsant Action 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bernard, P., Bergen, K., Sobiski, R., and Robson, R.D., 1981a, CGS 8216 (2-phenylpyrazolol4,3-c]quinolin-3(5H)-one), an orally effective benzodiazepine antagonist, Pharmacologist 23:150.Google Scholar
  2. Bernard, P., Wilson, D.E., Sobiski, R., and Robson, R.D., 1981b, Antagonism of diazepam-induced sedation and alcohol potentiation by CGS 8216 (2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one) in the rat, Soc. Neurosci. Abstr. 7:862.Google Scholar
  3. Braestrup, D., Nielsen, M., and Olsen, C.E., 1980, Urinary and brain 3-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors, Proc. Natl. Acad. Sci. USA 77:2288.PubMedCrossRefGoogle Scholar
  4. Braestrup, C., Schmiechen, R., Neef, G., Nielsen, M., and Petersen, E., 1982, Interaction of convulsive ligands with benzodiazepine receptors, Science 216:1241.CrossRefGoogle Scholar
  5. Corda, M., Blaker, W., Mendelson, W., and Guidotti, A., 1983, 6-Carbolines enhance the shock-induced suppression of drinking in the rat, Proc. Natl. Acad. Sci. USA 80:2072.PubMedCrossRefGoogle Scholar
  6. Dorow, R., Horowski, R., Paschelke, G., Amin, M., and Braestrup, C., 1983, Severe anxiety induced by FG 7142, a β-carboline ligand for benzodiazepine receptors, Lancet 9:98.CrossRefGoogle Scholar
  7. File, S., Lister, R., and Nutt, D., 1982, Intrinsic actions of benzodiazepine antagonists, Neurosci. Lett. 32:165.PubMedCrossRefGoogle Scholar
  8. Hunkeler, W., Möhler, H., Pieri, L., Pole, P., Bonetti, E., Cumin, R., Schaffner, R., and Haefely, W., 1981, Selective antagonists of benzodiazepines, Nature 290:514.PubMedCrossRefGoogle Scholar
  9. Insel, T., Ninan, P., Aloi, J., Jimerson, D., Skolnick, P., and Paul, S., 1984, A new psychopharmacologic model of anxiety, Arch. Gen. Psych., in press.Google Scholar
  10. Möhler, H., and Richards, J., 1983, Receptors for anxiolytic drugs, in: “Anxiolytics: Neurochemical, Behavioral and Clinical Perspectives,” J. Malick, S. Enna, and H. Yamamura, eds., Raven Press, New York.Google Scholar
  11. Ninan, P., Insel, T., Cohen, R., Cook, J., Skolnick, P., and Paul, S., 1982, Benzodiazepine receptor-mediated experimental “anxiety” in primates, Science 218:1332.PubMedCrossRefGoogle Scholar
  12. Oakley, N., and Jones, B., 1980, The proconvulsant and diazepam- reversing effects of ethyl-ß-carboline-3-carboxylate, Eur. J. Pharmacol. 68:381.PubMedCrossRefGoogle Scholar
  13. Schweri, M., Cain, M., Cook, J., Paul, S., and Skolnick, P., 1982, Blockade of 3-carbomethoxy-3-carboline induced Scizures by diazepam and the benzodiazepine antagonists, Ro 15–1788 and CGS 8216, Pharmacol. Biochem. Behav. 17:457.PubMedCrossRefGoogle Scholar
  14. Schweri, M., Martin, J., Mendelson, W., Barrett, J., Paul, S., and Skolnick, P., 1983, Pharmacokinetic and pharmacodynamic factors contributing to the convulsant action of ß-carboline-3-carboxyl- ate esters, Life Sci. 33:1505.PubMedCrossRefGoogle Scholar
  15. Skolnick, P., and Paul, S., 1981, Benzeodiazepine receptors, in: “Annual Reports in Medicinal Chemistry, Vol. 16, H.J. Hess, ed., Academic Press, New York.Google Scholar
  16. Skolnick, P., Hommer, D., and Paul, S., 1982, Benzodiazepine antagonists, in: “Pharmacology of Benzodiazepines,” E. Usdin, P. Skolnick, J. Tallman, D. Greenblatt, and S. Paul, eds., MacMillan Publishing Co., London.Google Scholar
  17. Skolnick, P., and Paul, S., 1983, New concepts in the neurobiology of anxiety, J. Clin. Psychiatry 44:12.PubMedGoogle Scholar
  18. Squires, R., 1981, GABA receptors regulate the affinities of anions required for brain specific benzodiazepine binding, in: “GABA and Benzodiazepine Receptors,” E. Costa, G. Di Chiara, and G. Gessa, eds., Raven Press, New York.Google Scholar
  19. Tenen, S., and Hirsch, J., 1980, ß-Carboline-3-carboxylic acid ethyl ester antagonizes diazepam activity, Nature 288:609.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1985

Authors and Affiliations

  • P. Skolnick
    • 1
  • P. Ninan
    • 1
  • T. Insel
    • 1
  • J. Crawley
    • 1
  • S. Paul
    • 1
  1. 1.NIADDK and NIMH, National Institutes of Health and AlcoholDrug Abuse and Mental Health AdministrationBethesdaUSA

Personalised recommendations