TY - JOUR
T1 - Clozapine and GABA transmission in schizophrenia disease models
T2 - Establishing principles to guide treatments
AU - O'Connor, William T.
AU - O'Shea, Sean D.
N1 - Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class.
AB - Schizophrenia disease models are necessary to elucidate underlying changes and to establish new therapeutic strategies towards a stage where drug efficacy in schizophrenia (against all classes of symptoms) can be predicted. Here we summarise the evidence for a GABA dysfunction in schizophrenia and review the functional neuroanatomy of five pathways implicated in schizophrenia, namely the mesocortical, mesolimbic, ventral striopallidal, dorsal striopallidal and perforant pathways including the role of local GABA transmission and we describe the effect of clozapine on local neurotransmitter release. This review also evaluates psychotropic drug-induced, neurodevelopmental and environmental disease models including their compatibility with brain microdialysis. The validity of disease models including face, construct, etiological and predictive validity and how these models constitute theories about this illness is also addressed. A disease model based on the effect of the abrupt withdrawal of clozapine on GABA release is also described. The review concludes that while no single animal model is entirely successful in reproducing schizophreniform symptomatology, a disease model based on an ability to prevent and/or reverse the abrupt clozapine discontinuation-induced changes in GABA release in brain regions implicated in schizophrenia may be useful for hypothesis testing and for in vivo screening of novel ligands not limited to a single pharmacological class.
KW - Abrupt discontinuation
KW - Atypical antipsychotic
KW - Functional neuroanatomy
KW - Microdialysis
KW - Nerve pathway
KW - Pharmacircuitry
UR - http://www.scopus.com/inward/record.url?scp=84939958508&partnerID=8YFLogxK
U2 - 10.1016/j.pharmthera.2015.01.005
DO - 10.1016/j.pharmthera.2015.01.005
M3 - Review article
C2 - 25585121
AN - SCOPUS:84939958508
SN - 0163-7258
VL - 150
SP - 47
EP - 80
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
ER -