Dopamine Dysfunction in Schizophrenia

Schizophrenia presents with multiple clinical features, ranging from positive symptoms (hallucinations, delusions, and thought disorder) to negative symptoms (social withdrawal, poverty of speech and thought, flattening of affect, and lack of motivation) and disturbances in cognitive processes (attention, working memory, verbal fluency and learning, social cognition, and executive function). In the last decade, imaging methodology has confirmed that dopamine (DA) dysregulation plays a role within each of these clinical dimensions, and has yielded evidence that striatal DA is increased, and cortical DA transmission is altered. Furthermore, the studies indicated a direct relationship between striatal DA excess and the positive symptoms of the illness as well as the magnitude and speed of their response to antipsychotic treatment, while cognitive and negative symptoms were related to cortical DA dysfunction. New evidence from both animal studies and studies in prodromal patients suggests that both sets of symptoms may emerge in relation to the striatal dopaminergic excess, the mechanisms of which are not well understood. This chapter begins by describing the evidence derived from imaging studies using measures of cortical and subcortical dopaminergic parameters and then speculates on the cellular significance of the imaging findings. It then describes the information gained from animal models regarding regulation of DA function by other transmitters and the circuits that may be involved, possibly leading to the dopaminergic phenotype.