General Pharmacology of Clozapine

Abstract

Clozapine shows neuroleptic-like inhibition of locomotor activity and conditioned avoidance responding in rodents, although tolerance develops on repeated treatment. EEG-based studies show strong arousal-inhibiting activity of clozapine as well as neuroleptic-like effects on both caudate spindle duration and rat sleep-waking patterns. Effects such as apomorphine blockade, catalepsy and strong increases of plasma prolactin levels are not seen, however, and chronic treatment does not lead to dopamine D₂ receptor supersensitivity. Binding studies show clozapine's highest affinities to be for dopamine D₄, 5-HT_1c, 5-HT₂, α₁, muscarinic and histamine H₁ receptors, but moderate affinity is also seen for many other receptor subtypes. Microdialysis studies indicate a preferential interaction with striatal D₁ receptors, whereas autoradiographical studies indicate upregulation of D₁ and downregulation of 5-HT₂ receptors after chronic clozapine. Clarification of the mechanisms underlying clozapine's special attributes is often hampered by a failure to examine compounds which show a close chemical relationship to clozapine, but which produce extrapyramidal side-effects in man, such as clothiapine, loxapine and amoxapine.