Anti-Phencyclidine monoclonal antibody, clone 5B/8

Blonanserin differs from other antipsychotic drugs, such as risperidone and olanzapine, and exhibits a higher affinity for dopamine-D-2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D-3 receptors in the effect of blonanserin on the social deficit observed in an animal model of schizophrenia and sought to elucidate the molecular mechanism underlying its action. Mice received phencyclidine (PCP: 10 mg/kg/day, s.c.), a non-competitive N-methyl-o-aspartate (NMDA) receptor antagonist, once a day for 14 consecutive days. We then evaluated the sociability, using a social interaction test, and the expression of GluN1 subunit, an essential subunit of the NMDA receptors, in these mice. Blonanserin significantly ameliorated the PCP-induced social deficit, whereas olanzapine and haloperidol did not. This effect of blonanserin was antagonized by 7-OH-DPAT, a dopamine-D-3 receptor agonist, and SCH23390, a dopamine-D-1 receptor antagonist. However, the ameliorating effect of blonanserin was not inhibited by DOI , a serotonin 5-HT2A receptor agonist. The PCP-induced social deficit was also ameliorated by U99194, a dopamine-D-3 receptor antagonist and SKF38393, a dopamine-D-1 receptor agonist, being effects antagonized by 7-OH-DPAT or SCH23390. Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser(897) by protein kinase A (PKA) in the prefrontal cortex (PFC) in PCP-administered mice. These results suggest that activation of NMDA receptors due to Ser(897)-phosphorylation of GluN1 subunit, which is a step linked to dopamine-D-1 receptor-PKA signaling through dopamine-D-3 receptor antagonism in the PFC, is required for the ameliorating effect of blonanserin on the PCP-induced social deficit. These findings also provide in vivo evidence that blonanserin antagonism of the dopamine-D-3 receptors may be useful as a novel treatment strategy and that the dopamine-D-3 receptors can be a novel therapeutic target molecule for the social deficit observed in schizophrenia.

Many behavioral and biological effects of a psychoactive drug often undergo time-dependent change following even one single drug exposure. The present study examined whether one or two exposures of haloperidol, olanzapine or clozapine would also induce a time-dependent change in their behavioral effects in adolescent rats, and whether such a change vary between sexes. Adolescent Sprague-Dawley rats (< 40 days old) were first treated with one single injection of haloperidol (0.05 and 0.1 mg/kg, sc), clozapine (10.0 and 20.0 mg/kg, sc), 2 injections of olanzapine (1.0 and 2.0 mg/kg, sc) or vehicle, and tested in a conditioned avoidance response (CAR) model or a PCP (3.20 mg/kg, sc)-induced hyperlocomotion model to assess the drug's antipsychotic-like behavioral effects. One or three weeks later, rats were challenged with the drug and their avoidance responses and the PCP -induced hyperlocomotion were re-assessed. One-trial haloperidol and 2-trial olanzapine induced a sensitization, while 1-trial clozapine induced a tolerance effect. The 1-trial haloperidol sensitization was significantly higher at the 3-week time point than at 1-week point, especially in the females. Clozapine tolerance in the conditioned avoidance response model also exhibited the time-dependent increase in both sex groups. Olanzapine sensitization in the PCP model showed a time-dependent change in a sex-dependent fashion. Overall, the time-dependent antipsychotic sensitization and tolerance can be demonstrated in adolescent animals. Many pharmacological (e.g. specific drugs, drug doses), individual (e.g. male versus female) and environmental (e.g. specific behavioral models) factors play a role in the modulation of the strength of antipsychotic sensitization and tolerance.