Animal models for the evaluation of antipsychotic agents

Schizophrenia, the most serious among psychoses, has negative symptoms such as anhedonia, avolition and apathy, and cognitive defects in addition to positive symptoms such as hallucinations and delusions characterising all psychotic disorders. Traditional antipsychotics had dopamine D₂ receptor antagonism as their principal mechanism of action, with disabling extrapyramidal symptoms as corollary. Newer atypical agents with diverse receptor actions introduced to circumvent this issue, nevertheless, had varied side effects such as agranulocytosis, insulin resistance, seizures, and cardiac events. Also, symptoms in cognitive and negative domains do not respond well even to newer agents creating an unmet need. Designing a valid animal model with translational relevance for a complex disease such as schizophrenia is a tedious process. Induction or suppression of certain animal behaviours by test compounds (behavioural models) and antagonising effects induced by compounds with psychotic potential (pharmacological models) are the conventional models used. One among the major disadvantages with conventional models is that these paradigms are induced acutely and relate to aberration of a single neurotransmitter system, which is in sharp contrast to the chronic nature and interplay of multiple neurotransmitter systems in psychotic diseases. However, with progress in elucidation of disease mechanisms, novel models are generated utilising developmental, genetic, and environmental factors (neurodevelopmental models) to effectively reflect the human disease pathogenesis and clinical manifestations, but with paucity of studies assessing the impact of drugs on them. This review presents an overview of schizophrenia hypotheses, requisites of a valid animal model, available animal models with their advantages and disadvantages.