Dysregulation of dopamine and pathology of prefrontal neurons: neuroimaging studies in schizophrenia and related animal models.

Several brain abnormalities have been claimed in schizophrenia, but the pathophysiology of the disorder remains unclear. Of the many reported findings, two lines of research data have emerged as particularly consistent, involving pathology of dorsolateral prefrontal cortex and dysregulation of the dopamine system. Abnormal dorsolateral prefrontal cortical function has been implicated in a number of neuropsychological and neuroimaging studies (Weinberger et al. 1986; Weinberger, 1987; Braff et al. 1991; Goldberg & Gold, 1995; Andreasen et al, 1994; Frith et al, 1995, Callicott et al., 1998). Moreover, post mortem tissue studies have found evidence of subtle pathology of dorsolateral prefrontal glutamatergic neurons and of their connectivity (Selemon et al. 1995; Lewis, 1997; Perrone-Bizzozzero et al., 1996; Rajkowska et al., 1998). On the other hand, while involvement of dopamine in the pathophysiology of schizophrenia is uncontested, the true neurobiological mechanisms underlying its dysregulation are still unclear. The «dopaminergic hypothesis)) of schizophrenia, that suggested hyperactivity of central dopamine neurons, was based on indirect pharmacological evidence (Carlsson, 1988); for example, dopamimetic drugs such as amphetamine have psychotogenic properties and antipsychotic drugs, such as chlorpromazine, are dopamine antagonists. Efforts to measure directly dopamine concentrations,