Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Apr;114(8):1717–1723. doi: 10.1111/j.1476-5381.1995.tb14962.x

Contrasting effects of the imidazol(in)e alpha 2-adrenoceptor agonists, medetomidine, clonidine and UK 14,304 on extraneuronal levels of noradrenaline in the rat frontal cortex: evaluation using in vivo microdialysis and synaptosomal uptake studies.

J W Dalley 1, S C Stanford 1
PMCID: PMC1510391  PMID: 7599940

Abstract

1. In vivo microdialysis in halothane-anaesthetized rats and synaptosomal [3H]-noradrenaline uptake studies in vitro were used to evaluate the effects of imidazole (medetomidine) and imidazoline (clonidine and UK 14,304) alpha 2-adrenoceptor agonists on extraneuronal levels of noradrenaline in the frontal cortex. 2. Levels of noradrenaline in the dialysate were increased by a depolarizing concentration of K+ (60 mM for 20 min) and substantially attenuated by reducing Ca2+ supply in the perfusate. These results suggest that spontaneous efflux of noradrenaline in the cortex is regulated predominantly by cation-dependent exocytotic mechanisms. 3. At a low perfusion concentration (0.5 microM), medetomidine, clonidine and UK 14,304 all reduced the level of noradrenaline in cortical dialysates. Continuous perfusion of the selective alpha 2-adrenoceptor antagonist, atipamezole (0.5 microM) caused a sustained increase in noradrenaline efflux and reversed the inhibitory effects of medetomidine. All these changes are consistent with drug actions at presynaptic alpha 2-adrenoceptors. 4. Higher concentrations of medetomidine (5-50 microM), but not clonidine or UK 14,304, evoked a non-desensitizing increase in noradrenaline efflux. This effect was not antagonized by 0.5 microM atipamezole. 5. The tricyclic noradrenaline reuptake inhibitor, desmethylimipramine (0.5-50 microM), increased noradrenaline efflux in a concentration-dependent manner. 6. The specific uptake of [3H]-noradrenaline into cortical synaptosomes was inhibited by medetomidine and desmethylimipramine with IC50 values of approximately 7 microM and 8 microM respectively. Neither clonidine nor UK 14,304 inhibited [3H]-noradrenaline uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
1721

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  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. Bidet M., Poujeol P., Parini A. Effect of imidazolines on Na+ transport and intracellular pH in renal proximal tubule cells. Biochim Biophys Acta. 1990 May 9;1024(1):173–178. doi: 10.1016/0005-2736(90)90221-9. [DOI] [PubMed] [Google Scholar]
  3. Bloor B. C., Frankland M., Alper G., Raybould D., Weitz J., Shurtliff M. Hemodynamic and sedative effects of dexmedetomidine in dog. J Pharmacol Exp Ther. 1992 Nov;263(2):690–697. [PubMed] [Google Scholar]
  4. De Langen C. D., Hogenboom F., Mulder A. H. Presynaptic noradrenergic alpha-receptors and modulation of 3H-noradrenaline release from rat brain synaptosomes. Eur J Pharmacol. 1979 Nov 23;60(1):79–89. doi: 10.1016/0014-2999(79)90054-2. [DOI] [PubMed] [Google Scholar]
  5. De Vos H., Bricca G., De Keyser J., De Backer J. P., Bousquet P., Vauquelin G. Imidazoline receptors, non-adrenergic idazoxan binding sites and alpha 2-adrenoceptors in the human central nervous system. Neuroscience. 1994 Apr;59(3):589–598. doi: 10.1016/0306-4522(94)90179-1. [DOI] [PubMed] [Google Scholar]
  6. Dennis T., L'Heureux R., Carter C., Scatton B. Presynaptic alpha-2 adrenoceptors play a major role in the effects of idazoxan on cortical noradrenaline release (as measured by in vivo dialysis) in the rat. J Pharmacol Exp Ther. 1987 May;241(2):642–649. [PubMed] [Google Scholar]
  7. Doze V. A., Chen B. X., Maze M. Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors. Anesthesiology. 1989 Jul;71(1):75–79. doi: 10.1097/00000542-198907000-00014. [DOI] [PubMed] [Google Scholar]
  8. Göthert M., Schlicker E., Köstermann F. Relationship between transmitter uptake inhibition and effects of alpha-adrenoceptor agonists on serotonin and noradrenaline release in the rat brain cortex. Naunyn Schmiedebergs Arch Pharmacol. 1983 Mar;322(2):121–128. doi: 10.1007/BF00512384. [DOI] [PubMed] [Google Scholar]
  9. Hills J. M., Sellers A. J., Mistry J., Broekman M., Howson W. Phosphinic acid analogues of GABA are antagonists at the GABAB receptor in the rat anococcygeus. Br J Pharmacol. 1991 Jan;102(1):5–6. doi: 10.1111/j.1476-5381.1991.tb12121.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. L'Heureux R., Dennis T., Curet O., Scatton B. Measurement of endogenous noradrenaline release in the rat cerebral cortex in vivo by transcortical dialysis: effects of drugs affecting noradrenergic transmission. J Neurochem. 1986 Jun;46(6):1794–1801. doi: 10.1111/j.1471-4159.1986.tb08498.x. [DOI] [PubMed] [Google Scholar]
  11. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  12. Langeloh A., Trendelenburg U. The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: role of monoamine oxidase and of vesicularly stored 3H-noradrenaline. Naunyn Schmiedebergs Arch Pharmacol. 1987 Dec;336(6):611–620. doi: 10.1007/BF00165751. [DOI] [PubMed] [Google Scholar]
  13. Limberger N., Starke K., Singer E. A. Serotonin uptake blockers influence serotonin autoreceptors by increasing the biophase concentration of serotonin and not through a "molecular link". Naunyn Schmiedebergs Arch Pharmacol. 1990 Oct;342(4):363–370. doi: 10.1007/BF00169450. [DOI] [PubMed] [Google Scholar]
  14. MacDonald E., Scheinin H., Scheinin M. Behavioural and neurochemical effects of medetomidine, a novel veterinary sedative. Eur J Pharmacol. 1988 Dec 6;158(1-2):119–127. doi: 10.1016/0014-2999(88)90260-9. [DOI] [PubMed] [Google Scholar]
  15. MacDonald E., Scheinin M., Scheinin H., Virtanen R. Comparison of the behavioral and neurochemical effects of the two optical enantiomers of medetomidine, a selective alpha-2-adrenoceptor agonist. J Pharmacol Exp Ther. 1991 Nov;259(2):848–854. [PubMed] [Google Scholar]
  16. Maura G., Bonanno G., Raiteri M. Presynaptic alpha 2-adrenoceptors mediating inhibition of noradrenaline and 5-hydroxytryptamine release in rat cerebral cortex: further characterization as different alpha 2-adrenoceptor subtypes. Naunyn Schmiedebergs Arch Pharmacol. 1992 Apr;345(4):410–416. doi: 10.1007/BF00176618. [DOI] [PubMed] [Google Scholar]
  17. Medgett I. C., McCulloch M. W., Rand M. J. Partial agonist of clonidine on prejunctional and postjunctional alpha-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1978 Oct;304(3):215–221. doi: 10.1007/BF00507961. [DOI] [PubMed] [Google Scholar]
  18. Michel M. C., Regan J. W., Gerhardt M. A., Neubig R. R., Insel P. A., Motulsky H. J. Nonadrenergic [3H]idazoxan binding sites are physically distinct from alpha 2-adrenergic receptors. Mol Pharmacol. 1990 Jan;37(1):65–68. [PubMed] [Google Scholar]
  19. Michel M., Hiemke C., Ghraf R. Preferential uptake of norepinephrine into dopaminergic terminals of a synaptosomal preparation from rat cerebral cortex. Brain Res. 1984 May 28;301(1):149–152. doi: 10.1016/0006-8993(84)90413-x. [DOI] [PubMed] [Google Scholar]
  20. Miralles A., Olmos G., Sastre M., Barturen F., Martin I., Garcia-Sevilla J. A. Discrimination and pharmacological characterization of I2-imidazoline sites with [3H]idazoxan and alpha-2 adrenoceptors with [3H]RX821002 (2-methoxy idazoxan) in the human and rat brains. J Pharmacol Exp Ther. 1993 Mar;264(3):1187–1197. [PubMed] [Google Scholar]
  21. Olmos G., Gabilondo A. M., Miralles A., Escriba P. V., García-Sevilla J. A. Chronic treatment with the monoamine oxidase inhibitors clorgyline and pargyline down-regulates non-adrenoceptor [3H]-idazoxan binding sites in the rat brain. Br J Pharmacol. 1993 Mar;108(3):597–603. doi: 10.1111/j.1476-5381.1993.tb12848.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pertovaara A. Antinociception induced by alpha-2-adrenoceptor agonists, with special emphasis on medetomidine studies. Prog Neurobiol. 1993 Jun;40(6):691–709. doi: 10.1016/0301-0082(93)90011-g. [DOI] [PubMed] [Google Scholar]
  23. Raiteri M., Bonanno G., Maura G., Pende M., Andrioli G. C., Ruelle A. Subclassification of release-regulating alpha 2-autoreceptors in human brain cortex. Br J Pharmacol. 1992 Dec;107(4):1146–1151. doi: 10.1111/j.1476-5381.1992.tb13421.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Redfern W. S., MacKinnon A. C., Brown C. M., Martin A. B., Kilpatrick A. T., Clague R. U., Spedding M. Modulation of central noradrenergic function by RS-15385-197. Br J Pharmacol. 1993 Feb;108(2):526–533. doi: 10.1111/j.1476-5381.1993.tb12835.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Reichenbacher D., Reimann W., Starke K. alpha-Adrenoceptor-mediated inhibition of noradrenaline release in rabbit brain cortex slices. Receptor properties and role of the biophase concentration of noradrenaline. Naunyn Schmiedebergs Arch Pharmacol. 1982 Apr;319(1):71–77. doi: 10.1007/BF00491481. [DOI] [PubMed] [Google Scholar]
  26. Renouard A., Widdowson P. S., Cordi A. [3H]-idazoxan binding to rabbit cerebral cortex recognises multiple imidazoline I2-type receptors: pharmacological characterization and relationship to monoamine oxidase. Br J Pharmacol. 1993 Jul;109(3):625–631. doi: 10.1111/j.1476-5381.1993.tb13618.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sammet S., Graefe K. H. Kinetic analysis of the interaction between noradrenaline and Na+ in neuronal uptake: kinetic evidence for CO-transport. Naunyn Schmiedebergs Arch Pharmacol. 1979 Nov;309(2):99–107. doi: 10.1007/BF00501216. [DOI] [PubMed] [Google Scholar]
  28. Sandberg M., Butcher S. P., Hagberg H. Extracellular overflow of neuroactive amino acids during severe insulin-induced hypoglycemia: in vivo dialysis of the rat hippocampus. J Neurochem. 1986 Jul;47(1):178–184. doi: 10.1111/j.1471-4159.1986.tb02847.x. [DOI] [PubMed] [Google Scholar]
  29. Savola J. M., Virtanen R. Central alpha 2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine. Eur J Pharmacol. 1991 Mar 26;195(2):193–199. doi: 10.1016/0014-2999(91)90535-x. [DOI] [PubMed] [Google Scholar]
  30. Starke K. Presynaptic alpha-autoreceptors. Rev Physiol Biochem Pharmacol. 1987;107:73–146. [PubMed] [Google Scholar]
  31. Tesson F., Prip-Buus C., Lemoine A., Pegorier J. P., Parini A. Subcellular distribution of imidazoline-guanidinium-receptive sites in human and rabbit liver. Major localization to the mitochondrial outer membrane. J Biol Chem. 1991 Jan 5;266(1):155–160. [PubMed] [Google Scholar]
  32. Trendelenburg U. The uptake and metabolism of 3H-catecholamines in rat cerebral cortex slices. Naunyn Schmiedebergs Arch Pharmacol. 1989 Mar;339(3):293–297. doi: 10.1007/BF00173580. [DOI] [PubMed] [Google Scholar]
  33. Virtanen R., Savola J. M., Saano V., Nyman L. Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist. Eur J Pharmacol. 1988 May 20;150(1-2):9–14. doi: 10.1016/0014-2999(88)90744-3. [DOI] [PubMed] [Google Scholar]
  34. Wikberg J. E., Uhlén S., Chhajlani V. Medetomidine stereoisomers delineate two closely related subtypes of idazoxan (imidazoline) I-receptors in the guinea pig. Eur J Pharmacol. 1991 Feb 14;193(3):335–340. doi: 10.1016/0014-2999(91)90148-j. [DOI] [PubMed] [Google Scholar]
  35. Wood M. D., Wyllie M. G. Critical assessment of noradrenaline uptake in synaptosomal preparations. Naunyn Schmiedebergs Arch Pharmacol. 1983 Mar;322(2):129–135. doi: 10.1007/BF00512385. [DOI] [PubMed] [Google Scholar]
  36. Zier G., Drobny H., Valenta B., Singer E. A. Evidence against a functional link between noradrenaline uptake mechanisms and presynaptic alpha-2 adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1988 Jan;337(1):118–121. doi: 10.1007/BF00169488. [DOI] [PubMed] [Google Scholar]
  37. van Veldhuizen M. J., Feenstra M. G., Boer G. J., Westerink B. H. Microdialysis studies on cortical noradrenaline release: basic characteristics, significance of extracellular calcium and massive post-mortem increase. Neurosci Lett. 1990 Nov 13;119(2):233–236. doi: 10.1016/0304-3940(90)90841-v. [DOI] [PubMed] [Google Scholar]
  38. van Veldhuizen M. J., Feenstra M. G., Heinsbroek R. P., Boer G. J. In vivo microdialysis of noradrenaline overflow: effects of alpha-adrenoceptor agonists and antagonists measured by cumulative concentration-response curves. Br J Pharmacol. 1993 Jul;109(3):655–660. doi: 10.1111/j.1476-5381.1993.tb13623.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES