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. 1996 Mar;117(6):1286–1292. doi: 10.1111/j.1476-5381.1996.tb16727.x

Modelling the changes induced by chronic desipramine treatment on the factors governing the agonism at prejunctional alpha 2-adrenoceptors.

J Sallés 1, J Giraldo 1, E Vila 1, A Badia 1
PMCID: PMC1909766  PMID: 8882627

Abstract

1. The adaptational changes induced after chronic desipramine treatment on functional responsiveness of alpha 2-adrenoceptor activation were investigated in prostatic portions of the rat vas deferens. 2. For this purpose, clonidine and xylazine were studied for their effects on twitch contractions elicited by electrical field stimulation of prostatic portions removed 48 h after the last injection to the animals of vehicle or desipramine (10 mg kg-1, i.p.; 14 days). Operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 300 nM) on the alpha 2-adrenoceptor-mediated effects of clonidine, either in vehicle- or in desipramine-treated animals. 3. Treatment with desipramine decreased the potency (increased the EC50) of clonidine and xylazine by about 12 and 9 fold respectively. However, the treatment did not modify the maximal effect (alpha) elicited by either agonist. The estimates of apparent affinity for clonidine did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Estimates of tau values for both agonists revealed that chronic desipramine treatment resulted in significant decreases in the efficacy of agonists. However, desipramine treatment was not associated with significant changes in the affinity constant for clonidine while for xylazine, the operational model provided a higher estimate of KA (lower affinity) after desipramine treatment. 4. The results indicate a large receptor reserve at prejunctional alpha 2-adrenoceptors which is modulated by chronic desipramine treatment. 5. The comparison of results obtained after chronic desipramine exposure with those by using EEDQ suggests that chronic desipramine treatment is not a useful experimental intervention for the purpose of estimating agonist affinities and efficacies.

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Selected References

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  1. Adler C. H., Meller E., Goldstein M. Receptor reserve at the alpha-2 adrenergic receptor in the rat cerebral cortex. J Pharmacol Exp Ther. 1987 Feb;240(2):508–515. [PubMed] [Google Scholar]
  2. Badia A., Sallés J. Effects of St-587 on the alpha-adrenoceptors in the bisected rat vas deferens. J Pharm Pharmacol. 1989 Sep;41(9):612–616. doi: 10.1111/j.2042-7158.1989.tb06541.x. [DOI] [PubMed] [Google Scholar]
  3. Barrett V. J., Leff P., Martin G. R., Richardson P. J. Pharmacological analysis of the interaction between Bay K 8644 and 5-HT in rabbit aorta. Br J Pharmacol. 1986 Mar;87(3):487–494. doi: 10.1111/j.1476-5381.1986.tb10190.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Black J. W., Gerskowitch V. P., Leff P., Shankley N. P. Pharmacological analysis of beta-adrenoceptor-mediated agonism in the guinea-pig, isolated, right atrium. Br J Pharmacol. 1985 Mar;84(3):779–785. doi: 10.1111/j.1476-5381.1985.tb16161.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Black J. W., Leff P. Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci. 1983 Dec 22;220(1219):141–162. doi: 10.1098/rspb.1983.0093. [DOI] [PubMed] [Google Scholar]
  6. Black J. W., Leff P., Shankley N. P., Wood J. An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation. Br J Pharmacol. 1985 Feb;84(2):561–571. doi: 10.1111/j.1476-5381.1985.tb12941.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Blakeley A. G., Brown D. A., Cunnane T. C., French A. M., McGrath J. C., Scott N. C. Effects of nifedipine on electrical and mechanical responses of rat and guinea pig vas deferens. Nature. 1981 Dec 24;294(5843):759–761. doi: 10.1038/294759a0. [DOI] [PubMed] [Google Scholar]
  8. Charney D. S., Menkes D. B., Heninger G. R. Receptor sensitivity and the mechanism of action of antidepressant treatment. Implications for the etiology and therapy of depression. Arch Gen Psychiatry. 1981 Oct;38(10):1160–1180. doi: 10.1001/archpsyc.1981.01780350094011. [DOI] [PubMed] [Google Scholar]
  9. Cohen R. M., Campbell I. C., Cohen M. R., Torda T., Pickar D., Siever L. J., Murphy D. L. Presynaptic noradrenergic regulation during depression and antidepressant drug treatment. Psychiatry Res. 1980 Sep;3(1):93–105. doi: 10.1016/0165-1781(80)90051-7. [DOI] [PubMed] [Google Scholar]
  10. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  11. Dougall I. G., Leff P. Pharmacological analysis of the calcium-dependence of mu-receptor agonism. Br J Pharmacol. 1987 Dec;92(4):723–731. doi: 10.1111/j.1476-5381.1987.tb11376.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Finberg J. P., Tal A. Reduced peripheral presynaptic adrenoceptor sensitivity following chronic antidepressant treatment in rats. Br J Pharmacol. 1985 Mar;84(3):609–617. doi: 10.1111/j.1476-5381.1985.tb16140.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fleming W. W., Westfall D. P., De la Lande I. S., Jellett L. B. Log-normal distribution of equiefective doses of norepinephrine and acetylcholine in several tissues. J Pharmacol Exp Ther. 1972 May;181(2):339–345. [PubMed] [Google Scholar]
  14. Fuder H., Braun H. J., Schimkus R. Presynaptic alpha-2 adrenoceptor activation and coupling of the receptor-presynaptic effector system in the perfused rat heart: affinity and efficacy of phenethylamines and imidazoline derivatives. J Pharmacol Exp Ther. 1986 Apr;237(1):237–245. [PubMed] [Google Scholar]
  15. García-Sevilla J. A., Zubieta J. K. Activation and desensitization of presynaptic alpha 2-adrenoceptors after inhibition of neuronal uptake by antidepressant drugs in the rat vas deferens. Br J Pharmacol. 1986 Dec;89(4):673–683. doi: 10.1111/j.1476-5381.1986.tb11171.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Giralt M. T., García-Sevilla J. A. Acute and long-term regulation of brain alpha 2-adrenoceptors after manipulation of noradrenergic transmission in the rat. Eur J Pharmacol. 1989 May 30;164(3):455–466. doi: 10.1016/0014-2999(89)90253-7. [DOI] [PubMed] [Google Scholar]
  17. Hyland L., Docherty J. R. Further examination of the effects of ageing on the adrenoceptor responsiveness of the rat vas deferens. Eur J Pharmacol. 1985 Apr 2;110(2):241–246. doi: 10.1016/0014-2999(85)90217-1. [DOI] [PubMed] [Google Scholar]
  18. James M. K., Morgan P. H., Leighton H. J. A new method for estimation of agonist dissociation constants (KA): directly fitting the postinactivation concentration-response curve to a nested hyperbolic equation. J Pharmacol Exp Ther. 1989 Apr;249(1):61–69. [PubMed] [Google Scholar]
  19. Leff P., Giles H. Classification of platelet and vascular prostaglandin D2 (DP) receptors: estimation of affinities and relative efficacies for a series of novel bicyclic ligands. With an appendix on goodness-of-fit analyses. Br J Pharmacol. 1992 Aug;106(4):996–1003. doi: 10.1111/j.1476-5381.1992.tb14447.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Leff P., Martin G. R., Morse J. M. Application of the operational model of agonism to establish conditions when functional antagonism may be used to estimate agonist dissociation constants. Br J Pharmacol. 1985 Jul;85(3):655–663. doi: 10.1111/j.1476-5381.1985.tb10561.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Leff P., Prentice D. J., Giles H., Martin G. R., Wood J. Estimation of agonist affinity and efficacy by direct, operational model-fitting. J Pharmacol Methods. 1990 May;23(3):225–237. doi: 10.1016/0160-5402(90)90066-t. [DOI] [PubMed] [Google Scholar]
  22. Lenox R. H., Ellis J., Van Riper D., Ehrlich Y. H. Alpha 2-adrenergic receptor-mediated regulation of adenylate cyclase in the intact human platelet. Evidence for a receptor reserve. Mol Pharmacol. 1985 Jan;27(1):1–9. [PubMed] [Google Scholar]
  23. MacDonald A., McGrath J. C. The distribution of adrenoceptors and other drug receptors between the two ends of the rat vas deferens as revealed by selective agonists and antagonists. Br J Pharmacol. 1980;71(2):445–458. doi: 10.1111/j.1476-5381.1980.tb10957.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Manji H. K. G proteins: implications for psychiatry. Am J Psychiatry. 1992 Jun;149(6):746–760. doi: 10.1176/ajp.149.6.746. [DOI] [PubMed] [Google Scholar]
  25. Meana J. J., Barturen F., García-Sevilla J. A. Alpha 2-adrenoceptors in the brain of suicide victims: increased receptor density associated with major depression. Biol Psychiatry. 1992 Mar 1;31(5):471–490. doi: 10.1016/0006-3223(92)90259-3. [DOI] [PubMed] [Google Scholar]
  26. Sallés J., Giraldo J., Badia A. Analysis of agonism at functional prejunctional alpha 2-adrenoceptors of rat vas deferens using operational and null approaches. Eur J Pharmacol. 1994 Jun 13;258(3):229–238. doi: 10.1016/0014-2999(94)90484-7. [DOI] [PubMed] [Google Scholar]
  27. Starke K. Presynaptic receptors. Annu Rev Pharmacol Toxicol. 1981;21:7–30. doi: 10.1146/annurev.pa.21.040181.000255. [DOI] [PubMed] [Google Scholar]
  28. Vila E., Sallés J., Badia A. Effects of chronic antidepressant treatment on alpha 1- and alpha 2-adrenoceptors in the rat anococcygeus muscle. J Neural Transm Gen Sect. 1990;82(3):205–212. doi: 10.1007/BF01272763. [DOI] [PubMed] [Google Scholar]

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