Comparison of the new atypical antipsychotics olanzapine and ICI 204,636 with clozapine on behavioural responses to the selective “D1-like” dopamine receptor agonist A 68930 and selective “D2-like” agonist RU 24213

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Abstract
The effects of the putative atypical antipsychotics olanzapine and ICI 204,636 on behavioural responses to the selective “D2-like” dopamine receptor agonist RU 24213 and to the selective “D1-like” agonist A 68930 were compared with those of the prototype atypical antipsychotic clozapine, the selective D1-like antagonist SCH 23390 and the selective D2-like antagonist YM 09151-2. Olanzapine (0.4–2.0 mg/kg) and ICI 204,636 (4.0–36.0 mg/kg), like clozapine (4.0–36.0 mg/kg) and SCH 23390 (0.01–1.0 mg/kg), effected at best modest reduction in typical sniffing and locomotor responses and, with the exception of ICI 204,636, released episodes of atypical myoclonic jerking to RU 24213 (12.5 mg/kg); a high dose of olanzapine (10.0 mg/kg), like YM 09151-2 (0.005–0.5 mg/kg), blocked all responsivity to RU 24213. Conversely, olanzapine (0.4–2.0 mg/kg) and ICI 204,636 (4.0–36.0 mg/kg), like clozapine (4.0–12.0 mg/kg) and SCH 23390 (0.01–0.1 mg/kg), readily blocked typical grooming responses to A 68930 (0.5 mg/kg); YM 09151-2 failed to block grooming and exerted more variable effects. Olanzapine and, to a lesser extent, ICI 204,636 share with clozapine a preferential action to attenuate D1-mediated function; given their lack of selective affinity for D1-like receptors, this common effect may be exerted at an alternative level of synaptic function. The action of olanzapine and particularly ICI 204,636 to release additional episodes of atypical vacuous chewing to A 68930 indicates some deviation from a wholly clozapine-like profile, the clinical significance of which remains to be specified.

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