The dopamine hypothesis postulates that the symptoms of schizophrenia result from dysregulation of dopamine in the CNS. Four dopaminergic anatomical pathways are described in this model. The mesolimbic pathway projects from the ventral tegmental area (VTA) to limbic areas. Excessive mesolimbic dopamine may lead to positive symptoms of schizophrenia, such as delusions and hallucinations. The mesocortical pathway projects from VTA to cortex, particularly prefrontal cortex. Low mesocortical dopamine is proposed to cause the negative symptoms and cognitive deficits of schizophrenia. The nigrostriatal pathway, from the substantia nigra to the striatum, regulates movements; low nigrostriatal dopamine leads to Parkinsonian motor symptoms. The tuberoinfundibular pathway travels from the hypothalamus to the pituitary gland and inhibits prolactin secretion; blockade of tuberoinfundibular dopamine leads to elevated prolactin and resultant galactorrhea, amenorrhea, and decreased libido. There remains some controversy over the role of excess mesolimbic dopamine in psychosis. On the one hand, drug effects support this model: Dopamine agonists such as amphetamines and cocaine provoke psychotic symptoms in normal subjects and those with schizophrenia; likewise, effective antipsychotic drugs bind and block the D2 subtype of dopamine receptors. Early studies showed increased dopamine metabolites and dopamine receptors in schizophrenia. Positron emission tomography (PET) imaging studies confirm increased synthesis of dopamine, increased levels of synaptic dopamine, and increased dopamine release in response to stressors such as amphetamine challenge. On the other hand, increased levels of mesolimbic dopamine and dopamine receptors have not been consistently shown across studies and remain controversial. Furthermore, many cases of schizophrenia are unresponsive to D2 blockade. Finally, some antipsychotic drugs, such as the atypical agent clozapine, have relatively poor D2 binding, which suggests that other neurotransmitters or receptors may be involved. On the whole, current evidence appears to support a central role for striatal D2 receptors in acute psychosis. The role of low mesocortical dopamine in negative and cognitive symptoms is also controversial. On the one hand, a correlation has been shown between low levels of dopamine metabolites in cerebrospinal fluid (CSF), low cortical dopamine, and the poor performance on working memory tasks are seen in schizophrenia. Likewise, dopamine agonists improve prefrontal activation and cognitive performance in schizophrenia. Yet postmortem studies have not clearly shown altered dopamine receptor levels in prefrontal cortex in patients with schizophrenia. PET studies have shown increased, decreased, or unchanged receptor levels, depending on the radiotracer used. It has been proposed that increases may actually reflect compensation for low prefrontal dopamine levels; this would make the significance of either an increase or decrease unclear. It is possible that the ongoing controversies over the role of dopamine in positive and negative symptoms results in part from the crudeness of available measuring techniques. Dopamine is thought to help define and “sharpen” cortical representations of sensation and action, enhancing salient patterns and dampening nonsalient ones. Attempting to explain brain dysfunction in terms of simple increases or decreases in dopamine may therefore be as futile as trying to measure the accuracy of a drawing by how much ink it contains. Subtle dysregulation of dopamine, whether in prefrontal cortex or striatum, could cause major deficits in information processing without overall excess or lack of dopamine. The Glutamate Hypothesis The glutamate hypothesis proposes that dysfunction of the N-methyl-D-aspartate (NMDA) glutamate receptor is the primary deficit underlying all the positive, negative, and cognitive symptoms of schizophrenia. Glutamate is the major excitatory neurotransmitter in the CNS. The NMDA receptor plays key roles in attention, perception, and cognition. Importantly, this receptor also plays critical roles in developmental processes such as axonal guidance, synaptic pruning, and plasticity, both in utero and during adolescence. For these reasons, the NMDA receptor is an attractive target for schizophrenia research. As with the dopamine hypothesis, the glutamate hypothesis originates in early findings of low glutamate levels in the CSF of patients with schizophrenia, and in the observation that the effects of NMDA antagonist drugs (ketamine, phencyclidine [PCP]) mimic some of the positive, negative, and cognitive features of schizophrenia. Postmortem studies show changes in the expression of NMDA receptors and their related proteins in schizophrenia. Many genes conferring schizophrenia risk appear to interact with the NMDA receptor in some way (such as GRM3, described earlier). Recent PET imaging also suggests reduced hippocampal NMDA receptor binding in schizophrenia. Glutamate models may be able to accommodate existing dopamine-centered hypotheses on schizophrenia. In one model, reduced prefrontal glutamate neurotransmission leads to reduced prefrontal activity. This results in decreased mesocortical activity, causing negative and cognitive symptoms. It also results in a loss of regulation in the mesolimbic projections. This pathway becomes hyperresponsive to stress or pharmacological challenge, leading to acute episodes of psychosis. Of note here, cannabis reduces corticostriatal glutamate release, while D2 receptor blockade increases glutamate release. Dopamine–glutamate models may be able to explain how cannabis and dopamine agonists provoke psychosis, and how D2 antagonists improve positive symptoms. Glutamate-centered theories offer a potential means of unifying genetic, developmental, neuropathological, and neurochemical understanding of schizophrenia. Lines of supporting evidence for NMDA-related dysfunction in schizophrenia are beginning to emerge. Research over the next few years should determine whether this trend continues, and whether the glutamate hypothesis can inspire new approaches to treatment.