Antagonism of the hypothermic effect of clozapine in mice by centrally-active α₂-adrenergic antagonists and α₁-adrenergic agonists

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.