Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1989 Jan;96(1):133–143. doi: 10.1111/j.1476-5381.1989.tb11793.x

The thermogenic actions of alpha 2-adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic alpha 2-adrenoceptor mechanism.

D J Bill 1, I E Hughes 1, R J Stephens 1
PMCID: PMC1854293  PMID: 2564288

Abstract

1. The dose-related effects of the selective alpha 2-adrenoceptor agonists clonidine, UK-14,304 and B-HT 933 on the body temperature of untreated and reserpine-treated mice were investigated. 2. In untreated mice all three agonists induced a dose-related hypothermia. The highest doses of UK-14,304 and B-HT 933, 3 and 100 mg kg-1 respectively, elicited a marked (10 degrees C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.5 degrees C) was less pronounced and reached a plateau at a dose of 0.5 mg kg-1 i.p. 3. Reserpine (2.5 mg kg-1, s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5-1.5 degrees C) above ambient (19 degrees C). 4. All three alpha 2-agonists produced a partial dose-related reversal of reserpine-induced hypothermia; maximal thermogenic responses (9-10 degrees C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16 mg kg-1 i.p. of clonidine, UK-14,304 and B-HT 933 respectively, and the log dose-response curves for all 3 agonists were bell-shaped. 5. Following intracerebroventricular administration to reserpine-treated mice, the thermogenic response to clonidine was more rapid in onset, and the agonist was 20 fold more potent than when injected i.p. 6. The selective alpha 2-adrenoceptor antagonists, idazoxan (0.05-0.5 mg kg-1), Wy 26392 (0.3-5.0 mg kg-1) and yohimbine (0.1-1.6 mg kg-1) given orally attenuated the thermogenic responses to all 3 agonists in reserpinized mice in a dose-related manner. Pretreatment with a single dose of idazoxan (0.3 mg kg-1, orally) elicited a 6 fold parallel shift to the right in the dose-response curve to clonidine. 7. The selective alpha 1-adrenoceptor antagonists, prazosin (10 mg kg-1) and indoramin (3-10 mg kg-1), and the beta-adrenoceptor antagonist, propranolol (10 mg kg-1), only partially attenuated the thermogenic responses to the alpha 2-agonists in reserpinized mice. These effects were variable and not clearly dose-related. 8. Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, markedly attenuated (60-95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13-12.5 mg kg-1, i.p.), but only slightly reduced (10-35%) that to clonidine (0.032-0.5 mg kg-1, i.p.). 9. These results suggest that alpha2-adrenoceptor agonists reverse reserpine-induced hypothermia via a central mechanism involving activation of postsynaptic alpha 2-adrenoceptors.

Full text

PDF
135

Selected References

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

  1. ASKEW B. M. A SIMPLE SCREENING PROCEDURE FOR IMIPRAMINE-LIKE ANTIDEPRESSANT AGENTS. Life Sci. 1963 Oct;10:725–730. doi: 10.1016/0024-3205(63)90076-6. [DOI] [PubMed] [Google Scholar]
  2. Andén N. E., Grabowska M., Strömbom U. Different alpha-adrenoreceptors in the central nervous system mediating biochemical and functional effects of clonidine and receptor blocking agents. Naunyn Schmiedebergs Arch Pharmacol. 1976;292(1):43–52. doi: 10.1007/BF00506488. [DOI] [PubMed] [Google Scholar]
  3. Berridge T. L., Gadie B., Roach A. G., Tulloch I. F. alpha 2-Adrenoceptor agonists induced mydriasis in the rat by an action within the central nervous system. Br J Pharmacol. 1983 Mar;78(3):507–515. doi: 10.1111/j.1476-5381.1983.tb08810.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brittain R. T. The intracerebral effects of noradrenaline and its modification by drugs in the mouse. J Pharm Pharmacol. 1966 Sep;18(9):621–623. doi: 10.1111/j.2042-7158.1966.tb07944.x. [DOI] [PubMed] [Google Scholar]
  5. Cambridge D. UK-14,304, a potent and selective alpha2-agonist for the characterisation of alpha-adrenoceptor subtypes. Eur J Pharmacol. 1981 Jul 10;72(4):413–415. doi: 10.1016/0014-2999(81)90588-4. [DOI] [PubMed] [Google Scholar]
  6. Cedarbaum J. M., Aghajanian G. K. Catecholamine receptors on locus coeruleus neurons: pharmacological characterization. Eur J Pharmacol. 1977 Aug 15;44(4):375–385. doi: 10.1016/0014-2999(77)90312-0. [DOI] [PubMed] [Google Scholar]
  7. Dausse J. P., Le Quan-Bui K. H., Meyer P. Alpha 1- and alpha 2-adrenoceptors in rat cerebral cortex: effects of neonatal treatment with 6-hydroxydopamine. Eur J Pharmacol. 1982 Feb 19;78(1):15–20. doi: 10.1016/0014-2999(82)90367-3. [DOI] [PubMed] [Google Scholar]
  8. Delini-Stula A., Baumann P., Büch O. Depression of exploratory activity by clonidine in rats as a model for the detection of relative pre- and postsynaptic central noradrenergic receptor selectivity of alpha-adrenolytic drugs. Naunyn Schmiedebergs Arch Pharmacol. 1979 Jun;307(2):115–122. doi: 10.1007/BF00498452. [DOI] [PubMed] [Google Scholar]
  9. Deniard M. J., Meignen J., DeFeudis F. V. Reversal of reserpine-induced ptosis in the mouse by alpha-adrenoceptor-agonists. Psychopharmacology (Berl) 1983;80(3):243–248. doi: 10.1007/BF00436162. [DOI] [PubMed] [Google Scholar]
  10. Doxey J. C., Roach A. G., Smith C. F. Studies on RX 781094: a selective, potent and specific antagonist of alpha 2-adrenoceptors. Br J Pharmacol. 1983 Mar;78(3):489–505. doi: 10.1111/j.1476-5381.1983.tb08809.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Drew G. M., Gower A. J., Marriott A. S. Alpha 2-adrenoceptors mediate clonidine-induced sedation in the rat. Br J Pharmacol. 1979 Sep;67(1):133–141. [PMC free article] [PubMed] [Google Scholar]
  12. Eriksson E., Edén S., Modigh K. Up- and down- regulation of central postsynaptic alpha 2 receptors reflected in the growth hormone response to clonidine in reserpine-pretreated rats. Psychopharmacology (Berl) 1982;77(4):327–331. doi: 10.1007/BF00432764. [DOI] [PubMed] [Google Scholar]
  13. Górka Z., Zacny E. The effect of single and chronic administration of imipramine on clonidine-induced hypothermia in the rat. Life Sci. 1981 Jun 22;28(25):2847–2854. doi: 10.1016/0024-3205(81)90100-4. [DOI] [PubMed] [Google Scholar]
  14. Heal D. J. Phenylephrine-induced activity in mice as a model of central alpha 1-adrenoceptor function. Effects of acute and repeated administration of antidepressant drugs and electroconvulsive shock. Neuropharmacology. 1984 Nov;23(11):1241–1251. doi: 10.1016/0028-3908(84)90040-6. [DOI] [PubMed] [Google Scholar]
  15. Langer S. Z. Presynaptic regulation of catecholamine release. Biochem Pharmacol. 1974 Jul 1;23(13):1793–1800. doi: 10.1016/0006-2952(74)90187-7. [DOI] [PubMed] [Google Scholar]
  16. Mogilnicka E., Klimek V., Nowak G., Czyrak A. Clonidine and a beta-agonists induce hyperthermia in rats at high ambient temperature. J Neural Transm. 1985;63(3-4):223–235. doi: 10.1007/BF01252027. [DOI] [PubMed] [Google Scholar]
  17. Paciorek P. M., Pierce V., Shepperson N. B., Waterfall J. F. An investigation into the selectivity of a novel series of benzoquinolizines for alpha 2-adrenoceptors in vivo. Br J Pharmacol. 1984 May;82(1):127–134. doi: 10.1111/j.1476-5381.1984.tb16449.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pettibone D. J., Pflueger A. B., Totaro J. A. Tetrabenazine-induced depletion of brain monoamines: mechanism by which desmethylimipramine protects cortical norepinephrine. Eur J Pharmacol. 1984 Jul 20;102(3-4):431–436. doi: 10.1016/0014-2999(84)90563-6. [DOI] [PubMed] [Google Scholar]
  19. Ross S. B. Antagonism of reserpine-induced hypothermia in mice by some beta-adrenoceptor agonists. Acta Pharmacol Toxicol (Copenh) 1980 Nov;47(5):347–350. doi: 10.1111/j.1600-0773.1980.tb01570.x. [DOI] [PubMed] [Google Scholar]
  20. SHORE P. A. Release of serotonin and catecholamines by drugs. Pharmacol Rev. 1962 Dec;14:531–550. [PubMed] [Google Scholar]
  21. Timmermans P. B., van Zwieten P. A. Mini-review. The postsynaptic alpha 2-adrenoreceptor. J Auton Pharmacol. 1981 Mar;1(2):171–183. doi: 10.1111/j.1474-8673.1981.tb00509.x. [DOI] [PubMed] [Google Scholar]
  22. U'Prichard D. C., Bechtel W. D., Rouot B. M., Snyder S. H. Multiple apparent alpha-noradrenergic receptor binding sites in rat brain: effect of 6-hydroxydopamine. Mol Pharmacol. 1979 Jul;16(1):47–60. [PubMed] [Google Scholar]
  23. Wagner J., Vitali P., Palfreyman M. G., Zraika M., Huot S. Simultaneous determination of 3,4-dihydroxyphenylalanine, 5-hydroxytryptophan, dopamine, 4-hydroxy-3-methoxyphenylalanine, norepinephrine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid in rat cerebrospinal fluid and brain by high-performance liquid chromatography with electrochemical detection. J Neurochem. 1982 May;38(5):1241–1254. doi: 10.1111/j.1471-4159.1982.tb07897.x. [DOI] [PubMed] [Google Scholar]
  24. Wakade A. R. A comparison of rates of depletion and recovery of noradrenaline stores of peripheral and central noradrenergic neurones after reserpine administration: importance of neuronal activity. Br J Pharmacol. 1980 Jan;68(1):93–98. doi: 10.1111/j.1476-5381.1980.tb10703.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES