caa a22 4500 465737781 CHVBK 20180323111759.0 cr unu---uuuuu 170327e19900501xx s 000 0 eng 10.1007/BF02253720 doi (NATIONALLICENCE)springer-10.1007/BF02253720 Antagonism of the hypothermic effect of clozapine in mice by centrally-active α2-adrenergic antagonists and α1-adrenergic agonists [Elektronische Daten] [M. Menon, R. Lloyd, L. Fitten] 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. Springer-Verlag, 1990 Clozapine nationallicence Clonidine nationallicence Adrenergic agonists nationallicence Adrenergic antagonists nationallicence Hypothermia nationallicence Menon M. Psychopharmacology Research, Veterans Administration Medical Center, 91343, Sepulveda, CA, USA aut Lloyd R. Psychopharmacology Research, Veterans Administration Medical Center, 91343, Sepulveda, CA, USA aut Fitten L. Psychopharmacology Research, Veterans Administration Medical Center, 91343, Sepulveda, CA, USA aut Psychopharmacology Springer-Verlag 101/1(1990-05-01), 67-72 0033-3158 101:1<67 1990 101 213 https://doi.org/10.1007/BF02253720 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF02253720 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Menon M. Psychopharmacology Research, Veterans Administration Medical Center, 91343, Sepulveda, CA, USA aut NATIONALLICENCE 700 1- Lloyd R. Psychopharmacology Research, Veterans Administration Medical Center, 91343, Sepulveda, CA, USA aut NATIONALLICENCE 700 1- Fitten L. Psychopharmacology Research, Veterans Administration Medical Center, 91343, Sepulveda, CA, USA aut NATIONALLICENCE 773 0- Psychopharmacology Springer-Verlag 101/1(1990-05-01), 67-72 0033-3158 101:1<67 1990 101 213 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer