Behavioral animal models of antipsychotic drug actions

Abstract

Basic research in animals represents a fruitful approach to study the neurobiological basis of brain and behavioral disturbances relevant to neuropsychiatric disease and to establish and evaluate novel pharmacological therapies for their treatment. In the context of schizophrenia, there are models employing specific experimental manipulations developed according to specific pathophysiological or etiological hypotheses. The use of selective lesions in adult animals and the acute administration of psychotomimetic agents are indispensable tools in the elucidation of the contribution of specific brain regions or neurotransmitters to the genesis of a specific symptom or collection of symptoms and enjoy some degrees of predictive validity. However, they may be inaccurate, if not inadequate, in capturing the etiological mechanisms or ontology of the disease needed for a complete understanding of the disease and may be limited in the discovery of novel compounds for the treatment of negative and cognitive symptoms of schizophrenia. Under the prevailing consensus of schizophrenia as a disease of neurodevelopmental origin, we have seen the establishment of neurodevelopmental animal models which aim to identify the etiological processes whereby the brain, following specific triggering events, develops into a "schizophrenia-like brain" over time. Many neurodevelopmental models such as the neonatal ventral hippocampus (vHPC) lesion, methylazoxymethanol (MAM), and prenatal immune activation models can mimic a broad spectrum of behavioral, cognitive, and pharmacological abnormalities directly implicated in schizophrenic disease. These models allow pharmacological screens against multiple and coexisting schizophrenia-related dysfunctions while incorporating the disease-relevant concept of abnormal brain development. The multiplicity of existing models is testimonial to the multifactorial nature of schizophrenia, and there are ample opportunities for their integration. Indeed, one ultimate goal must be to incorporate the successes of distinct models into one unitary account of the complex disorder of schizophrenia and to use such unitary approaches in the further development and evaluation of novel antipsychotic treatment strategies.