PM435. Targeting Functional Selectivity of the Dopamine D2 Receptor for Treatment of Schizophrenia-like Behaviors

Depression and anxiety is frequently seen in many schizophrenic patients and may be further aggravated or diminished by antipsychotic treatments. Haloperidol is a conventional antipsychotic used in schizophrenia and psychosis. Neutrophins are a family of structurally related proteins regulating the survival,differentiation, and maintance of function of different neuron populations. Fibroblast growth factor-2 (FGF2) has an important role in many aspects of CNS functioning. Synapsin, another key marker of synaptic activity plays an important role in hippocampally based behaviors. There is evidence that nevre growth factor (NGF) also mediates multiple biological phenomena. We aimed to investigate the effects of haloperidol on depression, anxiety and pain in naive mice, using forced swiming (FST), elevated plus maze (EPM) and hot plate tests. Since genes involved in neurite remodeling are among the primary targets of regulation, effects of haloperidol on expression levels of FGF2, synapsin and NGF in the hippocampus of mice were determined using quantitative RT-PCR. Mice were treated chronically with haloperidol (0.125 and 0.25 mg/kg;15 days, n=10/per group) and haloperidol was also administered intraperitoneally 60 min before the tests. Fluoxetine, diazepam or metamizol-sodium were used as reference drugs. The results of this study revealed that: (1) In the FST, fluoxetine significantly decreased immobility time (p<0.001) while haloperidol significantly increased (0.25 mg/kg, (p<0.05) this parameter. (2) In the EPM test, diazepam (p<0.001) and haloperidol (0.25 mg/kg) significantly increased % time spent in open arm’s and % open arm entries (p<0.001; p<0.01). (3) In the hot plate test, metamizol sodium (p<0.001) and haloperidol (0.125 mg/kg and 0.25 mg/kg, p<0.05, p<0.001 respectively) significantly increased the latency for licking the hindpaws. (4) Haloperidol significantly increased expression of FGF2 and synapsin while it decreased expression of NGF.Thus haloperidol exerts depression-,anxiolytic-like behaviour, analgesic effects and alters gen expression levels of FGF2, synapsin and NGF in mice. PM435 Targeting Functional Selectivity of the Dopamine D2 Receptor for Treatment of Schizophrenia-like Behaviors William Wetsel1, Marc G. Caron1, Jian Jin2, Su Mi Park1, Vladimir M. Pogorelov1, Ramona M. Rodriguiz1, Claire M. Schmerberg1 1Duke University Medical Center, USA, 2Icahn School of Medicine at