Animal Models of Psychosis

Abstract

Although the thinking and affective and social disturbances of psychosis and schizophrenia may not be easily modeled, if at all, in infrahuman species, animal models can clarify genetic and developmental lesions leading to disruption of some of the key anatomical circuitry involved in their pathophysiology. Increasingly, it is appreciated that patients with schizophrenia manifest symptoms in a variety of discrete domains of psychopathology, including positive (e.g., hallucinations), negative (e.g., affective flattening and social withdrawal), cognitive (e.g., concretization of thought), mood (e.g., anhedonia), and motor (e.g., mannerisms and posturing) symptoms. These symptoms may reflect, in part, the spatially and temporally integrated outputs from these disrupted or faulty circuits. Major goals of current descriptive and pathological research in schizophrenia include the development of sensitive behavioral rating instruments for the assessment of the presence and severity of symptoms in discrete psychopathological domains, elucidation of unique neurotransmitter abnormalities that may underlie each of these discrete domains of psychopathology, and determining the quantitative contribution of each of these discrete domains of psychopathology to the functional disability manifested by patients with schizophrenia and other psychosis. Thus, animal models that reflect nondopaminergic neurotransmitter abnormalities implicated in the pathophysiology of these discrete domains of psychopathology are especially useful. In addition to clarifying aspects of the pathophysiology of these disorders, animal models are crucial for identifying candidate compounds that may be developed as medications; novel medications are especially needed for the negative and cognitive symptom domains of psychopathology, which may be less dependent on abnormalities of dopaminergic neurotransmission. The contributions of dopaminergic abnormalities to the pathophysiology of schizophrenia have been studied most intensively. The focus on dopaminergic abnormalities in schizophrenia was prompted by the complementary observations in humans that psychosis can be elicited by psychostimulant medications such as d-amphetamine, especially when they are abused, whereas the ability to inhibit competitively the binding of dopamine to the D2 type of dopamine receptor is a pharmacological property shared by all of the conventional antipsychotic medications. Psychostimulant medications are either indirect or directly acting dopamine agonists. These pharmacological observations in humans stimulated interest in the quantitative characterization of a variety of “hardwired” rodent behaviors elicited by dopamine agonists such as apomorphine and d-amphetamine; these behaviors include a variety of stereotypic behaviors (e.g., rearing, grooming, and sniffing), horizontal locomotion and “mouse climbing,” among other behaviors. These animal procedures have served as valuable screens for the identification of “dopamine blockers” and medications whose primary pharmacological actions involve modulation (dampening) of dopaminergic neurotransmission, which have proven especially effective in the attenuation of positive symptoms. However, the negative and cognitive symptom domains of psychopathology, which contribute very significantly to the functional disability of schizophrenia and other psychotic disorders, are not dramatically affected by these primarily dopaminergic interventions. Thus, there is also intense interest in animal models that mimic neurodevelopmental abnormalities and/or disruptions of neurotransmitter systems other than dopamine. The existence of neurodevelopmental abnormalities in at least some patients with schizophrenia, as reflected in subtle histopathological abnormalities in cortical lamination, the orientation and alignment of neurons within the hippocampus, and diminished cortical neuropil, has heightened interest in the adult developmental consequences of neonatal lesions of the hippocampus, which, thereby, deprive the developing frontal cortex of afferent inputs from the hippocampus, and genetic models associated with altered cortical lamination, such as the reeler mouse.