An investigation of the anomalous low incidence of motor side effects of the novel antipsychotic drug - Y931

The quest for finding new antipsychotic drugs for schizophrenia, using clozapine as the model, with fewer side effects as compared to typical antipsychotic drugs, has produced quite a few new drugs in recent years. But none of these are completely free of extrapyramidal side effects (EPS), a condition that gets worse by prolonged use of antipsychotic drugs by some patients. In recent years, it has been hypothesized that a lower affinity towards dopamine D2 receptors and higher affinity for serotonin (especially at 5HT2c receptors) for the new drugs may cause their atypicality and lower EPS. Y931 is a new potential atypical antipsychotic drug. It is also classed as a multi-affinity receptor target agent. It is suggested that Y931 gives very few (if any) extrapyramidal side effects in animal models at standard medical dosage. Y931 has a similar receptor profile to clozapine and olanzapine. But unlike these and some other antipsychotic drugs, Y931 has relatively high affinity for dopamine D2 receptors. Thus some aspect of the pharmacology of Y931 could be different to clozapine and olanzapine and it may be working to suppress potential EPS generated by D2 antagonism in some different way than these drugs. Y931 has very high affinity for 5HT2C receptors. There are significant levels of 5HT2C receptor mRNA present in the terminal areas of the dopaminergic system, e.g., striatum and the nucleus accumbens. In vivo electrophysiological studies showed that the serotonergic system exerts an inhibitory action on the basal activity of midbrain DA- containing neurons. Thus it could be that there could be a functional relationship between serotonin and dopamine containing neurons, which could be either inhibition or facilitation of dopamine release. Several researchers showed that antagonism of 5HT2C receptors can affect dopaminergic modulation. The aim of this study is to investigate the characteristics and mechanisms of phannacological activity of Y931 in relation to extrapyramidal side effects. We used three different studies to analyse the compound Y931. Firstly, we studied the immediate early gene (EEG) induction profile of Y931 (10mg/kg, i.p.) together with haloperidol (1mg/kg, i.p.) and olanzapine (10mg/kg, i.p.) after 45 minutes following acute treatment. Secondly, we carried out a behavioural study on the effect of serotonin receptor antagonists using a 5HT2B/2C receptor antagonist (SB200646, 10 mg/kg, i.p) and a selective 5HT2C receptor (SB 242084) on haloperidol induced catalepsy. Thirdly, we studied the induction profile of some marker genes in the different regions of the basal ganglia, which may be involved in the process of EPS after acute treatment with antipsychotic drugs. Overall, the results suggest that Y931 tends to increase striato-pallidal activity and pallido- subthalamic activity. The contribution of 5HT2C receptor activity is not clear. The higher affinity of Y931 for serotonin receptors (5HT2C) did not seem to relate to the ability of Y931 to alter the activity of regions of the basal ganglia. The results suggest that Y931 affects striatal activity in a way predicted to lead to EPS. However, some action elsewhere in the basal ganglia may suppress this potential, although 5HT2C receptors are unlikely to be involved. (Abstract shortened by ProQuest.)