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-HT1c, 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.

Clozapine improves dizocilpine-induced delayed alternation impairment in rats

“…However, Katz and Schmaltz (1981) found that not only the NMDA antagonist amantadine but also the DA agonist apomorphine induced a spatial alternation impairment that is characterized by perseveration reflecting an abnormal attentional process. Since dizocilpine stimulates DA synthesis, release and metabolism Imperato, 1990;Svensson et al, 1992) one may argue that deficient learning of delayed alternation is DA-dependent and clozapine-induced improvement is brought about by its DA receptor blocking properties (see Coward, 1992). However, the DA stimulating effects of dizocilpine in the dose used here are weak (Rao etal., 1990) and behavioural stimulation produced by dizocilpine is still present in monoamine-depleted mice pretreated with haloperidol as shown by Carlsson and Carlsson (1989).…”

Effect of clozapine on interval timing and working memory for time in the peak-interval procedure with gaps

“…It binds to dopaminergic, serotonergic, H1 histaminergic, muscarinic acethylcholine, and α1-and α2-adrenergic receptors (King and Waddington, 2004;Leysen, 2000). Clozapine has relatively low affinity for the D2 receptors in the striatum (Xiberas et al, 2001), while its in vitro affinity for the D4 receptors is much higher than that for D1, D2, D3, and D5 receptors (Coward, 1992;Kusumi et al, 1995). This accounts for the efficacy of clozapine in alleviating the symptoms of schizophrenia without causing extra pyramidal side effects (Farde et al, 1992), because D4 receptor density is high in the frontal cortex and amygdala but relatively low in the basal ganglia (De La Garza and Madras, 2000;Tarazi et al, 1998).…”

Inhibitory Action of Clozapine on Rat Ventral Tegmental Area Dopamine Neurons Following Increased Levels of Endogenous Kynurenic Acid

“…During the last decade, large efforts have been made to understand the mode of antipsychotic action of clozapine, but despite a large number of studies, our knowledge remains fragmentary. It is established that clozapine not only interacts with all DA receptors (the D 4 subtype showing the highest affinity (19 nM; Van Tol et al, 1991)), but also with other metabotropic receptors, for example, those for serotonin (5HT 1 and 5HT 2 ; Canton et al, 1990), acetylcholine (Snyder et al, 1974), noradrenaline (see Coward, 1992), and histamine (see Brunello et al, 1995;see Coward, 1992). Previous studies also point to an interaction with some ionotropic receptors, for example, the N-methyl-D-aspartate (NMDA) receptor (Arvanov et al, 1997;Ossowska et al, 1999) and the GABA A receptor (Squires and Saederup, 1998).…”