Neurochemistry of Schizophrenia: Glutamatergic Abnormalities

Multiple neurotransmitters have been implicated in schizophrenia. Dopamine is the neurotransmitter most often hypothesized to be associated with the pathophysiology of schizophrenia for two reasons. First, dopaminergic agonists can cause or exacerbate psychotic symptoms. Second, the correlation between antipsychotic efficacy and D2 dopamine-receptor blockade is excellent. For these reasons, a number of postmortem studies have focused on the dopaminergic system in schizophrenic brain. Although the results of these studies have generally been negative, the few positive findings have rarely been replicated, with the notable exception of increased striatal D2-receptor expression, which may be secondary to prior neuroleptic treatment. These studies of dopaminergic abnormalities in postmortem brain in schizophrenia have been recently reviewed (1,2). Given the lack of findings associated with the dopamine system in the brain in schizophrenia, the elucidation of other potential neurotransmitter substrates of this illness has been an area of recent investigation. Glutamatergic dysfunction has been hypothesized to occur in schizophrenia, and this has been one of the most active areas of neurotransmitter research in this illness during the past few years. In this chapter, the glutamate hypothesis of schizophrenia is reviewed, the complexity of the molecules associated with the glutamate synapse is outlined, and postmortem neurochemical data suggesting glutamatergic abnormalities in schizophrenia are presented.