Antagonism of the hypothermic effect of clozapine in mice by centrally-active alpha 2-adrenergic antagonists and alpha 1-adrenergic agonists

Hypothermia induced by either clozapine or clonidine in mice was blocked by the alpha 2-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 greater than CH-38083 greater than yohimbine greater than idazoxan greater than 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 alpha 2-adrenergic antagonist, L-659,066, indicating that blockade by the other compounds occurred centrally. The centrally-acting, alpha 1-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 alpha 1-adrenergic receptors. This indicates that clozapine-induced hypothermia in mice is not a suitable model for evaluating the properties of central alpha 1-adrenergic compounds. Moreover, since the clonidine-induced hypothermia is not influenced by alpha 1-adrenergic agonists, this paradigm is preferable to clozapine-induced hypothermia in the assessment of alpha 2-adrenergic antagonism The ability of alpha 2-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.