ORG 5222 is a tetracyclic compound with high affinity for
dopamine and 5-HT2 receptors.
ORG 5222 was compared to
fluphenazine in behavioural tests and was shown to be less potent to cause
catalepsy on peripheral administration or to induce asymmetric body posturing following intrastriatal injection. On injection into the nucleus accumbens,
ORG 5222 antagonised spontaneous and
amphetamine-induced hyperactivity. The peripheral administration of
ORG 5222 antagonised the hyperactivity induced by infusion of
dopamine into the nucleus accumbens of rat or ventral striatum of the marmoset and, unlike the use of
fluphenazine, there was no evidence of a 'rebound' hyperactivity after discontinuation of treatment. Furthermore,
ORG 5222 prevented changes in responsiveness to
dopamine agonist challenge following
dopamine infusion. In a mouse black and white test box and the rat elevated plus maze
ORG 5222 released exploratory behaviour suppressed by the aversive white or elevated environments. It is concluded that
ORG 5222 is effective to antagonise mesolimbic
dopamine function in the rodent and primate and an aversive behaviour in rodent tests. Such effects reveal a novel profile of action of
ORG 5222 in behavioural paradigms predictive of
antipsychotic and
anxiolytic potential and may relate to a
dopamine and
5-HT receptor antagonism.