Abstract
Hypothermia induced by either clozapine or clonidine in mice was blocked by the α2-adrenergic antagonists yohimbine, idazoxan, CH-38083, SKF 86466, and L-657,743. These effects were dose related, and the ID50 values for inhibition of clozapine- or clonidine-induced hypothermia were fairly comparable. The order of potency for blocking clonidine-induced hypothermia was: L-657,743>CH-38083>yohimbine>idazoxan>SKF 86466. A very similar blockade hierarchy for clozapine-induced hypothermia was observed, with the order of the two most effective compounds being reversed. Hypothermia induced by either compound was not blocked by the peripherally-acting, selective α2-adrenergic antagonist, L-659,066, indicating that blockade by the other compounds occurred centrally. The centrally-acting, α1-adrenergic agonists St 587, cirazoline, and SKF 89748 were very effective in blocking the response to clozapine, but ineffective in antagonizing clonidine-induced hypothermia. The ED50 values for the blockade of this response to clozapine, however, did not correlate with their reported potencies in stimulating either peripheral or central α1-adrenergic receptors. This indicates that clozapine-induced hypothermia in mice is not a suitable model for evaluating the properties of central α1-adrenergic compounds. Moreover, since the clonidine-induced hypothermia is not influenced by α1-adrenergic agonists, this paradigm is preferable to clozapine-induced hypothermia in the assessment of α2-adrenergic antagonism. The ability of α2-adrenergic antagonists to block clozapine-induced hypothermia may result from the central overflow of norepinephrine, which is known to be brought about by this group of compounds. The neurochemical mechanism responsible for the anti-clozapine effect of the α1-adrenergic agonists in mice is not clear. An as yet unknown property of these compounds, unrelated to α1-agonism, may have to be considered. An interaction of these compounds at the high-affinity clozapine binding site is a possibility. Discovery of antagonists to clozapine may help to elucidate the mechanism of action of this atypical neuroleptic.
Similar content being viewed by others
References
Anden NE, Pauksens K, Svensson K (1982) Selective blockade of brain α2-autoreceptors by yohimbine: effects on motor activity and on turnover of noradrenaline and dopamine. J Neural Transm 55:111–120
Burki HR (1980) Inhibition of3H-clozapine binding in rat brain after oral administration of neuroleptics. Life Sci 26:2187–2193
Clineschmidt BV, Pettibone DJ, Lotti VJ, Hucker HB, Sweeney BM, Reiss DR, Lis EV, Huff JR, Vacca J (1988) A peripherally acting α2-adrenoceptor antagonist: L659,066. J Pharmacol Exp Ther 245:32–40
De Jonge A, Van Meel CA, Timmermans PBMWM, Van Zwieten PA (1981) A lipophilic selective α1-adrenoceptor agonist: 2-(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587). Life Sci 28:2009–2016
De Jonge A, Timmermans PBMWM, van Zwieten PA (1983) Quantitative aspects of α adrenergic effects induced by clonidine-like imidazolidines III. Comparison of central and peripheral α1 and α2 adrenoceptors. J Pharmacol Exp Ther 226:565–571
Delini-Stula A, Baumann P, Buch O (1979) Depression of exploratory activity of clonidine in rats as a model for the detection of relative pre- and postsynaptic central noradrenergic receptor selectivity of alpha-adrenolytic drugs. Naunyn-Schmiedeberg's Arch Pharmacol 307:115–122
Dennis T, L'Henreux R, Carter C, Scatton B (1987) Presynaptic alpha-2 adrenoceptor 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 241:642–649
Franklin KBJ, Herberg LJ (1977) Presynaptic alpha-adrenoceptors: the depression of self-stimulation by clonidine and its restoration by piperoxane but not by phentolamine or phenoxybenzamine. Eur J Pharmacol 43:33–38
Hauser D, Closse A (1978)3H-clozapine binding to rat brain membranes. Life Sci 23:557–562
Hayes AG, Skingle M, Tyers MB (1986) Antagonism of alpha-adrenoceptor agonist-induced antinociception in the rat. Neuropharmacology 25:397–402
Hieble JP, De Marines M, Fowler PJ, Matthews WD (1986) Selective alpha-2 adrenoceptor blockade by SKF 86466; in vitro characterization of receptor selectivity. J Pharmacol Exp Ther 236:90–96
Hieble JP, Sarau HM, Foley JJ, De Marinis RM, Pendleton RG (1982) Comparison of central and peripheral α1-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 318:267–273
Hornung R, Presek P, Glossmann H (1979) Alpha adrenoceptors in rat brain: Direct identification with prazosin. Naunyn-Schmiedeberg's Arch Pharmacol 308:223–230
Katz JL (1984) Effects of clonidine and some α-adrenergic antagonists alone and in combination on schedule controlled behavior in pigeons and mice. Psychopharmacology 83:38–43
Langer SZ (1981) Presynaptic regulation of the release of catecholamines. Pharmacol Rev 32:337–362
Marwaha J, Aghajanian GK (1982) Typical and atypical neuroleptics are potent antagonists at α1-adrenoceptors of the dorsal lateral geniculate nucleus. Naunyn-Schmiedeberg's Arch Pharmacol 321:32–37
van Meel JCA, De Jonge A, Timmermans PBMWM, van Zwieten PA (1981) Selectivity of some alpha adrenoceptor agonists for peripheral alpha-1 and alpha-2 adrenoceptors in the normotensive rat. J Pharmacol Exp Ther 219:760–767
Menon MK, Kodama CK, Kling AS, Fitten J (1986) An in vivo pharmacological method for the quantitative evaluation of the central effects of alpha-1 adrenoceptor agonists and antagonists. Neuropharmacology 25:503–508
Menon MK, Dinovo EC, Haddox VG (1987) Modification of certain pharmacological effects of ethanol by lipophilic alpha-1 adrenergic agonists. Life Sci 41:1599–1610
Menon MK, Gordon LI, Fitten J (1988) Interaction between clozapine and a lipophilic α1-adrenergic agonist. Life Sci 43:1791–1804
Nomura Y, Oki K, Segawa T (1980) Pharmacological characterization of central alpha-adrenoceptors which mediate clonidine-induced locomotor hyperactivity in the developing rat. Naunyn-Schmiedeberg's Arch Pharmacol 311:41–44
Paalzow G, Paalzow L (1976) Clonidine antinociceptive activity: effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 292:119–126
Peroutka SJ, Snyder SH (1980) Relationship of neuroleptic drug effects at brain serotonin, α-adrenergic and histamine receptors to clinical potency. Am J Psychiatry 137:1518–1522
Perry BD, Simons PR, U'Prichard DC (1983) Interactions of neuroleptic compounds at α2-adrenergic receptor affinity sites in bovine caudate nucleus. Eur J Pharmacol 95:315–318
Petersen EN (1981) Pre- and postsynaptic α-adrenoceptor antagonism by neuroleptics in vivo. Eur J Pharmacol 69:399–405
Pettibone DJ, Clineschmidt BV, Lotti VJ, Baldwin JJ, Huff JR, Randall WC, Vacca J, Young SD (1987) Pharmacological profile of a new potent and specific α2-adrenoceptor antagonist, L-657,643 Naunyn-Schmiedeberg's Arch Pharmacol 336:169–175
Pichler L, Kobinger W (1985) α2-Adrenoceptor blocking properties of the α1-selective agonist 2(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587). Arzneimittelforschung 35:201–205
Robson RD, Antanaccio MJ, Saelans JK, Liebman J (1978) Antagonism by mianserin and classical alpha-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine. Eur J Pharmacol 47:431–442
Ruffolo RR, Waddell (1982) Receptor interactions of imidazolines. IX. Cirazoline is an alpha-1 adrenergic agonist and an alpha-2-adrenergic antagonist. J Pharmacol Exp Ther 222:29–36
Scatton B, Dedak J, Zivkovic B (1983) Lack of involvement of α2-adrenoceptors in the regulation of striatal dopaminergic transmission. Eur J Pharmacol 86:427–433
Starke K (1977) Regulation of noradrenaline release by presynaptic receptor systems. Rev Physiol Biochem Pharmacol 77:1–124
Timmermans PBMWM, Matthews WD, Demarinis RM, Hieble JP, Mathy MJ, Doods HN, Thoolen MJMC, De Jonge A, Wilffert B, Van Zwietan PA (1984) α1-Adrenoceptor-mediated vasoconstriction in vivo to enantiomers of SKF 89748-A. Eur J Pharmacol 101:45–55
Vizi ES, Harsing LG, Gaal J, Kaposcsi J, Bernath S, Somogyi GT (1986) CH 38083, a selective potent antagonist of alpha-2 adrenoceptors. J Pharmacol Exp Ther 238:701–706
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Menon, M.K., Lloyd, R.L. & Fitten, L.J. Antagonism of the hypothermic effect of clozapine in mice by centrally-active α2-adrenergic antagonists and α1-adrenergic agonists. Psychopharmacology 101, 67–72 (1990). https://doi.org/10.1007/BF02253720
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02253720