Interaction between clozapine and a lipophilic alpha 1-adrenergic agonist

Acute intraperitoneal injection of clozapine produced marked hypothermia and ataxia in Swiss-Webster mice. These two effects were almost completely blocked by the lipophilic alpha 1-adrenergic agonist, St 587, but not by the peripherally-acting alpha 1 agonist methoxamine. It was inferred that these effects of clozapine are central in origin and probably resulted from alpha 1 adrenergic blockade. However, since prazosin, a selective alpha 1-adrenergic antagonist did not elicit either hypothermia or ataxia in mice it became clear that the alpha 1 adrenergic blocking effect of clozapine is not entirely responsible for these effects, but has a major contributory role in their production. Both clozapine and prazosin inhibited the d-amphetamine-induced locomotor stimulation in mice. St 587 did not significantly reduce this amphetamine-blocking effect of clozapine. It was inferred that this response to d-amphetamine involving the release of mesolimbic dopamine is distinct from the other two St 587-sensitive responses. The hypothermic and ataxic effects of clozapine developed complete tolerance after just four days of treatment, but ten days of such treatment was required for the development of tolerance to the amphetamine-blocking effect of clozapine. The possible relationships between St 587-sensitive and insensitive effects of clozapine and its antipsychotic property are discussed.