PM440. The Effects of An Atypical Antipsychotic on the Mr 32 kDa Related Signaling Pathways

Background: Aripiprazole is a D2 receptor (D2R) partial agonist with a favourable clinical profile, compared with other antipsychotics. Previous in vivo studies indicated that acute and short-term administration with aripiprazole affected the GSK3β (glycogen synthase kinase 3β)-dependent pathways, NMDA receptor and CREB (cAMP-responsive element-binding protein 1), which may contribute to its therapeutic efficacy. Aripiprazole is widely used for chronic treatment of various mental disorders, however the chronic effects of aripiprazole on cellular signalling are not clear. Aim: The present study investigated the chronic effects of aripiprazole on the relevant signalling pathways, in comparison with haloperidol (a D2R antagonist) and bifeprunox (a potent D2R partial agonist). Method: Rats were orally treated with aripiprazole (0.250 mg/ kg), bifeprunox (0.267 mg/kg), haloperidol (0.033 mg/kg) or vehicle three times per day for 10 weeks. The levels of Akt (protein kinase B)-GSK3β, Dvl (dishevelled)-β-catenin, NMDA-CREB1 signalling pathways were measured in the prefrontal cortex (PFC), caudate putamen (CPu) and nucleus accumbens (NAc) by Western Blots. Results: Akt-GSK3β pathway was activated by both aripiprazole and haloperidol in the PFC, and by all three drugs in the NAc. Both aripiprazole and bifeprunox increased the expression of Dvl-3 and β-catenin in the NAc. Both aripiprazole and haloperidol increased NMDA NR1 expression and CREB activity in the NAc; aripiprazole also promoted NMDA NR2A expression and CREB activity in the CPu. Conclusion: All drugs tested had chronic effects on Akt-GSK3β signalling. Aripiprazole and haloperidol had similar effects on Dvl-β-catenin and NMDA-CREB signalling in the NAc, which indicates that a D2R partial agonist with relatively low intrinsic activity may affect Dvl-β-catenin and NMDA-CREB signalling. The chronic effects of aripiprazole on these signalling pathways may contribute to its long-term clinical efficacy. PM440 The Effects of An Atypical Antipsychotic on the Mr 32 kDa Related Signaling Pathways Hanson Park, St. Andrew’s Hospital, Republic of Korea Abstract Introduction: In this study, we investigated changes in phosphorylation of Mr 32 kDa and ERK1/2 related signaling pathways in rat striatum, which is closely related to development of extrapyramidal symptom, after intraperitoneal injection of risperidone, which is one of the representative atypical antipsychotics, to facilitate understanding of the action mechanism of antipsychotic agents and regulatory mechanism of signal transduction of neuronal cell. Methods: Risperidone (0.5, 2.0 mg/kg) was injected into the Sprague-Dawley rats intraperitoneally and control animals received an equivalent volume of 0.3% tartaric acid. Western blot analysis was carried out to investigate the changes in Mr 32 kDa and ERK1/2 related molecules in response to risperidone treatment. Results: After 15, 30, 60 and 120min from treatment of risperidone (0.5 mg/kg), phosphorylations of MEK1/2 (Ser217/Ser221) and ERK1/2 (Thr202/Tyr204) were not changed, significantly. After 30 min from treatment of risperidone (2.0 mg/kg), phosphorylations of MEK1/2 were increased, significantly. After 120 min from treatment of risperidone (2.0 mg/kg), phosphorylations of ERK1/2 were increased, significantly. In terms of p90RSK (Thr360/Ser364), phosphorylations were increased after 30 and 60min from treatment of risperidone (2.0 mg/kg). Conclusions: Phosphorylations of ERK1/2, MEK1/2, and p90RSK were not changed after treatment of risperidone 0.5 mg/kg. Phosphorylations of ERK1/2, MEK1/2, and p90RSK after the injection of risperidone 2mg/kg were increased in some sample according to time-course. These findings suggest that risperidone may affect MEK1/2-ERK1/2-p90RSK pathway in the manner of time and dose specificity. In summary, time and dose dependant influence of risperidone on the signal transduction in striatum, which is responsible to the pathophysiology of schizophrenia and action mechanism of antipsychotics, might be related to unique properties of atypical antipsychotics include risperidone.Introduction: In this study, we investigated changes in phosphorylation of Mr 32 kDa and ERK1/2 related signaling pathways in rat striatum, which is closely related to development of extrapyramidal symptom, after intraperitoneal injection of risperidone, which is one of the representative atypical antipsychotics, to facilitate understanding of the action mechanism of antipsychotic agents and regulatory mechanism of signal transduction of neuronal cell. Methods: Risperidone (0.5, 2.0 mg/kg) was injected into the Sprague-Dawley rats intraperitoneally and control animals received an equivalent volume of 0.3% tartaric acid. Western blot analysis was carried out to investigate the changes in Mr 32 kDa and ERK1/2 related molecules in response to risperidone treatment. Results: After 15, 30, 60 and 120min from treatment of risperidone (0.5 mg/kg), phosphorylations of MEK1/2 (Ser217/Ser221) and ERK1/2 (Thr202/Tyr204) were not changed, significantly. After 30 min from treatment of risperidone (2.0 mg/kg), phosphorylations of MEK1/2 were increased, significantly. After 120 min from treatment of risperidone (2.0 mg/kg), phosphorylations of ERK1/2 were increased, significantly. In terms of p90RSK (Thr360/Ser364), phosphorylations were increased after 30 and 60min from treatment of risperidone (2.0 mg/kg). Conclusions: Phosphorylations of ERK1/2, MEK1/2, and p90RSK were not changed after treatment of risperidone 0.5 mg/kg. Phosphorylations of ERK1/2, MEK1/2, and p90RSK after the injection of risperidone 2mg/kg were increased in some sample according to time-course. These findings suggest that risperidone may affect MEK1/2-ERK1/2-p90RSK pathway in the manner of time and dose specificity. In summary, time and dose dependant influence of risperidone on the signal transduction in striatum, which is responsible to the pathophysiology of schizophrenia and action mechanism of antipsychotics, might be related to unique properties of atypical antipsychotics include risperidone. PM441 Long term atypical antipsychotic treatment improves cognitive performance in schizophrenia but not surpassing conventional antipsychotic drugs effects. Gabriel Selva Vera (1), Aroa Borrás Barrachina (2). (1) Teaching Unit of Psichiatry and Psychological Medicine. University of Valencia (Spain). (2) University Jaime I, Castellón (Spain). Abstract Background and Objectives: Atypical antipsychotics provide better control of the negative and affective symptoms of schizophrenia when compared with conventional neuroleptics. Nevertheless, their heightened ability to improve cognitive dysfunction remains a matter of debate. This study aimed to examine the changes in cognition associated with long-term antipsychotic treatment and to evaluate the effect of the type of antipsychotic (conventional versus novel antipsychotic drugs) on cognitive performance over time. Methods: In this naturalistic study, we used a comprehensive neuropsychological battery of tests to assess a sample of schizophrenia patients taking either conventional (n = 21) or novel antipsychotics (n = 32) at baseline and at two years after. These tests were used to measure seven neurocognitive domains, (Executive Functions, Working Memory, Verbal Memory, Visual Memory, Visual-Motor Processing, Semantic Verbal Fluency and Motor Speed). The clinical evaluation of each patient was rated according to the Positive and Negative Symptom Scale and to the Hamilton Rating Scale for Depression. Premorbid adjustment was assessed using the Phillips Adjustment Scale.Background and Objectives: Atypical antipsychotics provide better control of the negative and affective symptoms of schizophrenia when compared with conventional neuroleptics. Nevertheless, their heightened ability to improve cognitive dysfunction remains a matter of debate. This study aimed to examine the changes in cognition associated with long-term antipsychotic treatment and to evaluate the effect of the type of antipsychotic (conventional versus novel antipsychotic drugs) on cognitive performance over time. Methods: In this naturalistic study, we used a comprehensive neuropsychological battery of tests to assess a sample of schizophrenia patients taking either conventional (n = 21) or novel antipsychotics (n = 32) at baseline and at two years after. These tests were used to measure seven neurocognitive domains, (Executive Functions, Working Memory, Verbal Memory, Visual Memory, Visual-Motor Processing, Semantic Verbal Fluency and Motor Speed). The clinical evaluation of each patient was rated according to the Positive and Negative Symptom Scale and to the Hamilton Rating Scale for Depression. Premorbid adjustment was assessed using the Phillips Adjustment Scale.