- Email: [email protected]
PCP INDUCED SOCIAL BEHAVIOUR DEFICITS IN FEMALE RATS, IMPROVEMENT BY NOVEL BUT NOT CLASSICAL ANTIPSYCHOTICS, A POTENTIAL MODEL OF NEGATIVE SYMPTOMS
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
31 – PCP INDUCED SOCIAL BEHAVIOUR DEFICITS IN FEMALE RATS, IMPROVEMENT BY NOVEL BUT NOT CLASSICAL ANTIPSYCHOTICS, A POTENTIAL MODEL OF NEGATIVE SYMPTOMS
Shikha Snigdha, Joanna C. Neill University of Bradford, Bradford, UK [email protected] Introduction: Sub-chronic phencyclidine (PCP) treatment mimics aspects of schizophrenia atsymptomology in rats (Sams-Dodd 1999; Grayson et al. 2007). However, there is a marked lack of validated animal models of negative symptoms. The aim of this work was to establish such a model by inducing social interaction deficits in female rats and to investigate the efficacy of novel and classical antipsychotics to improve the deficits. Methods: Female hooded-Lister rats received vehicle (n=36) or PCP (n=22; 2mg/kg i.p.) twice daily for 7 days, followed by a 7-day washout period. On test days, PCP treated rats were treated acutely with either haloperidol (0.05 mg/kg) or ziprasidone (2.5mg/k g) and in a second experiment with either fluoxetine (2.5mg/kg) or chlordiazepoxide (CDP) (2.5mg/kg) all i.p., 30 min prior to testing. For the test, pairs of rats receiving either acute doses of drugs described above or vehicle were placed in the test arena and behaviors (following, sniffing, climbing over and under, exploration of inanimate object and avoiding) were recorded on video for scoring. Results: The results showed that PCP-induced deficits in social behaviors were attenuated by acute treatment with ziprasidone and fluoxetine but not haloperidol or CDP. Conclusions: These findings show that novel but not classical antipsychotic agents improve PCP induced social interaction deficits in female rats. The SSRI antidepressant, fluoxetine also shows efficacy. This suggests that PCP-induced deficits may be a potential model of negative symptoms of schizophrenia. Acknowledgements: Organon Laboratories References [1] Grayson B, Idris NF, Neill JC. (2007) Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav Brain Res. 184: 31-38 [2] Sams-Dodd F (1999): Phencyclidine in the social interaction test: an animal model of schizophrenia with face and predictive validity. Rev Neurosci; 10: 59-90
32 – ALTERNATIVE APPROACH TO MODULATING SCHIZOPHRENIA-ASSOCIATED GENES IN THE RODENT BRAIN
Catherine Winchester, David Thomson, Brian Morris, Judith Pratt PsyRING, Glasgow, Scotland [email protected] Introduction: Viral mediated gene transfer into specific sites within the brain allows precise manipulation of transgene expression in both time and space, thereby circumventing the disadvantages associated with conventional transgenic animal models. Methods: We have selected a vector derived from lentivirus, an RNA retrovirus that can transduce differentiated non-dividing cells, as well as dividing cells. The stable integration of reverse transcribed viral RNA into a host genome therefore enables long-term modifications for in vivo applications. To drive cell-type specific expression we have utilized a characterized promoter from a gene highly expressed in neurons of the forebrain. Results: Parallel microarray analyses of human schizophrenic post mortem tissue and a rodent PCP model of prefrontal cortex deficits (Cochran et al., 2003) identified differentially expressed genes from novel convergent pathways that are likely to be dysfunctional in schizophrenia. By generating lentiviral constructs containing some of these candidate genes we aim to modify their expression in the rat prefrontal cortex by stereotaxic injection. We have generated GFPcontaining lentiviral particles as a control for optimizing these in
67
vivo experiments and have assessed expression in infected neurons by immunohistochemistry. Conclusions: We provide data on the generation and evaluation of the lentiviral constructs and particles and preliminary in vivo expression of GFP in the prefrontal cortex. References [1] Cochran et al., (2003), Neuropsychopharmacology. 28 (2):265-275
33 – NEW FEATURES OF ATYPICAL ANTIPSYCHOTIC DRUG QUETIAPINE: REGULATING OLIGODENDROCYTE DEVELOPMENT AND REGENERATION, PREVENTING DEMYELINATION INDUCED BY CUPRIZONE
Yanbo Zhang 1 , Haiyun Xu 2 , Lan Xiao 3 , Zelan Wei 4 , Jue He 4 , Wengao Jiang 5 , Xiaokun Li 5 , Lillian Dyck 4 , Richard Devon 6 , Jiming Kong 7 , Xin-Min Li 1 1 Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba; 2 Department of Anatomy, Southern Illinois University School of Medicine, Springfield, Illinois; 3 Department of Anatomy, Third Military Medical University, Congqing, Congqing; eu; 4 Nueropsychiatry Research Unit, Department of Psychiatry, University of Saskatche, Saskatoon, Saskatchewan; 5 Laboratory of Neuropharmacology, Wenzhou Medical College, Wenzou, Zhejiang; 6 Department of Anatomy, University of Saskatchewan, Saskatoon, Saskatchewan; 7 Department of Anatomy, University of Manitoba, Winnipeg, Manitoba, Canada [email protected] Introduction: Schizophrenia is featured with alterations in oligodendrocytes (OLs) indicated by magnetic resonance imaging and micro-array analysis. However, little information is available regarding effects of antipsychotic drugs (APDs) on OLs. Methods: C57BL/6 mice were fed a 0.2% cuprizone-containing or control diet for 5 weeks and then removed to allow for remyelination. QTP (10mg/kg/day, P.O) or saline was administrated to mice in demyelination for 5 weeks or remyelination for 2 weeks. Rat embryonic neural stem cells were cultured from E17 fetus brain and treated with QTP (0.1-1 µm) for 6 days. Luxol fast blue staining was used for detecting the demyelination; Immunohistochemistry was used to detect mature and progenitor OLs, microglia and astrocyte. Western blotting was used to assay the extracellular signal-regulated kinase 2 (ERK-2) pathways. Results: Exposure of C57BL/6J mice to 5 weeks of 0.2% CPZ was optimal in producing demyelination and microglial and astrocyte activation. QTP co-administration significantly reduced the demyelination and cellular responses. Treatment with QTP promotes the mature OL relocating to the demyelinated area in remyelination process. QTP facilitates the maturation of OL and myelin forming in vitro medicating by activation of ERK-2 pathways. Conclusions: These findings suggest a new neural mechanism of antipsychotic action of QTP, and help to establish a role of oligodendrocytes in the etiopathology and treatment of schizophrenia. Acknowledgements: We thank the Canadian Psychiatric Research Foundation, The Canadian Institutes of Health Research, the Saskatchewan Health Research Foundation, and NeuroScience Canada for the support. References [1] Andreasen, N.N.C (2002)., Symptoms, signs, and diagnosis of schizophrenia. Lancet, The, 1995. 346(8973): p. 477-81. [2] Hof, P.R.P.R., et al., Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochemical Research, 27(10): p. 1193-200. [3] Flynn, S.S.W., et al. (2003) Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Molecular Psychiatry, 8(9): p. 811-20. [4] Tkachev, D.D., et al (2003)., Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362(9386): p. 798805.
31 – PCP INDUCED SOCIAL BEHAVIOUR DEFICITS IN FEMALE RATS, IMPROVEMENT BY NOVEL BUT NOT CLASSICAL ANTIPSYCHOTICS, A POTENTIAL MODEL OF NEGATIVE SYMPTOMS
Shikha Snigdha, Joanna C. Neill University of Bradford, Bradford, UK [email protected] Introduction: Sub-chronic phencyclidine (PCP) treatment mimics aspects of schizophrenia atsymptomology in rats (Sams-Dodd 1999; Grayson et al. 2007). However, there is a marked lack of validated animal models of negative symptoms. The aim of this work was to establish such a model by inducing social interaction deficits in female rats and to investigate the efficacy of novel and classical antipsychotics to improve the deficits. Methods: Female hooded-Lister rats received vehicle (n=36) or PCP (n=22; 2mg/kg i.p.) twice daily for 7 days, followed by a 7-day washout period. On test days, PCP treated rats were treated acutely with either haloperidol (0.05 mg/kg) or ziprasidone (2.5mg/k g) and in a second experiment with either fluoxetine (2.5mg/kg) or chlordiazepoxide (CDP) (2.5mg/kg) all i.p., 30 min prior to testing. For the test, pairs of rats receiving either acute doses of drugs described above or vehicle were placed in the test arena and behaviors (following, sniffing, climbing over and under, exploration of inanimate object and avoiding) were recorded on video for scoring. Results: The results showed that PCP-induced deficits in social behaviors were attenuated by acute treatment with ziprasidone and fluoxetine but not haloperidol or CDP. Conclusions: These findings show that novel but not classical antipsychotic agents improve PCP induced social interaction deficits in female rats. The SSRI antidepressant, fluoxetine also shows efficacy. This suggests that PCP-induced deficits may be a potential model of negative symptoms of schizophrenia. Acknowledgements: Organon Laboratories References [1] Grayson B, Idris NF, Neill JC. (2007) Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav Brain Res. 184: 31-38 [2] Sams-Dodd F (1999): Phencyclidine in the social interaction test: an animal model of schizophrenia with face and predictive validity. Rev Neurosci; 10: 59-90
32 – ALTERNATIVE APPROACH TO MODULATING SCHIZOPHRENIA-ASSOCIATED GENES IN THE RODENT BRAIN
Catherine Winchester, David Thomson, Brian Morris, Judith Pratt PsyRING, Glasgow, Scotland [email protected] Introduction: Viral mediated gene transfer into specific sites within the brain allows precise manipulation of transgene expression in both time and space, thereby circumventing the disadvantages associated with conventional transgenic animal models. Methods: We have selected a vector derived from lentivirus, an RNA retrovirus that can transduce differentiated non-dividing cells, as well as dividing cells. The stable integration of reverse transcribed viral RNA into a host genome therefore enables long-term modifications for in vivo applications. To drive cell-type specific expression we have utilized a characterized promoter from a gene highly expressed in neurons of the forebrain. Results: Parallel microarray analyses of human schizophrenic post mortem tissue and a rodent PCP model of prefrontal cortex deficits (Cochran et al., 2003) identified differentially expressed genes from novel convergent pathways that are likely to be dysfunctional in schizophrenia. By generating lentiviral constructs containing some of these candidate genes we aim to modify their expression in the rat prefrontal cortex by stereotaxic injection. We have generated GFPcontaining lentiviral particles as a control for optimizing these in
67
vivo experiments and have assessed expression in infected neurons by immunohistochemistry. Conclusions: We provide data on the generation and evaluation of the lentiviral constructs and particles and preliminary in vivo expression of GFP in the prefrontal cortex. References [1] Cochran et al., (2003), Neuropsychopharmacology. 28 (2):265-275
33 – NEW FEATURES OF ATYPICAL ANTIPSYCHOTIC DRUG QUETIAPINE: REGULATING OLIGODENDROCYTE DEVELOPMENT AND REGENERATION, PREVENTING DEMYELINATION INDUCED BY CUPRIZONE
Yanbo Zhang 1 , Haiyun Xu 2 , Lan Xiao 3 , Zelan Wei 4 , Jue He 4 , Wengao Jiang 5 , Xiaokun Li 5 , Lillian Dyck 4 , Richard Devon 6 , Jiming Kong 7 , Xin-Min Li 1 1 Department of Psychiatry, University of Manitoba, Winnipeg, Manitoba; 2 Department of Anatomy, Southern Illinois University School of Medicine, Springfield, Illinois; 3 Department of Anatomy, Third Military Medical University, Congqing, Congqing; eu; 4 Nueropsychiatry Research Unit, Department of Psychiatry, University of Saskatche, Saskatoon, Saskatchewan; 5 Laboratory of Neuropharmacology, Wenzhou Medical College, Wenzou, Zhejiang; 6 Department of Anatomy, University of Saskatchewan, Saskatoon, Saskatchewan; 7 Department of Anatomy, University of Manitoba, Winnipeg, Manitoba, Canada [email protected] Introduction: Schizophrenia is featured with alterations in oligodendrocytes (OLs) indicated by magnetic resonance imaging and micro-array analysis. However, little information is available regarding effects of antipsychotic drugs (APDs) on OLs. Methods: C57BL/6 mice were fed a 0.2% cuprizone-containing or control diet for 5 weeks and then removed to allow for remyelination. QTP (10mg/kg/day, P.O) or saline was administrated to mice in demyelination for 5 weeks or remyelination for 2 weeks. Rat embryonic neural stem cells were cultured from E17 fetus brain and treated with QTP (0.1-1 µm) for 6 days. Luxol fast blue staining was used for detecting the demyelination; Immunohistochemistry was used to detect mature and progenitor OLs, microglia and astrocyte. Western blotting was used to assay the extracellular signal-regulated kinase 2 (ERK-2) pathways. Results: Exposure of C57BL/6J mice to 5 weeks of 0.2% CPZ was optimal in producing demyelination and microglial and astrocyte activation. QTP co-administration significantly reduced the demyelination and cellular responses. Treatment with QTP promotes the mature OL relocating to the demyelinated area in remyelination process. QTP facilitates the maturation of OL and myelin forming in vitro medicating by activation of ERK-2 pathways. Conclusions: These findings suggest a new neural mechanism of antipsychotic action of QTP, and help to establish a role of oligodendrocytes in the etiopathology and treatment of schizophrenia. Acknowledgements: We thank the Canadian Psychiatric Research Foundation, The Canadian Institutes of Health Research, the Saskatchewan Health Research Foundation, and NeuroScience Canada for the support. References [1] Andreasen, N.N.C (2002)., Symptoms, signs, and diagnosis of schizophrenia. Lancet, The, 1995. 346(8973): p. 477-81. [2] Hof, P.R.P.R., et al., Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochemical Research, 27(10): p. 1193-200. [3] Flynn, S.S.W., et al. (2003) Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Molecular Psychiatry, 8(9): p. 811-20. [4] Tkachev, D.D., et al (2003)., Oligodendrocyte dysfunction in schizophrenia and bipolar disorder. Lancet 362(9386): p. 798805.