These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.

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The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamineinduced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [1231] The dopamine hypothesis of schizophrenia, formulated over 30 years ago, proposes that hyperactivity of dopaminergic transmission is associated with this illness (1). This hypothesis is based on the observation that dopamine D2 receptor antagonists alleviate symptoms of the illness (mostly positive symptoms), while dopamine agonists can induce psychotic states characterized by some salient features of schizophrenia (2). These pharmacological effects suggest, but do not establish, a dysregulation of dopamine systems in schizophrenia. Despite decades of effort to validate this hypothesis, documentation of abnormalities of dopamine function in schizophrenia has remained elusive. Postmortem studies measuring dopamine and its metabolites in the brain of schizophrenic patients have yielded inconsistent results (for review, see ref.3). Increased density of striatal dopamine D2 and D2-like receptors has been reported in postmortem studies, but this observation is difficult to interpret, given that neuroleptic drugs upregulate these receptors (4, 5). Positron emission tomography and single photon emission computerized tomography (SPECT) studies of striatal D2 and D2-like receptors density in neurolepticnaive schizophrenic patients have been inconclusive. While one group reported increased striatal D2-like receptors density in schizophrenia (6, 7), other groups reported negative results (8-12). The lack of clear evidence for increased dopaminergic indices in schizophrenia might indicate that dopaminergic transmission is enhanced only relative to other systems, such as serotonergic or glutamatergic systems (13,14). On the other hand, the absence of data supporting the dopamine hypothesis of schizophrenia might be due to the difficulty of obtaining direct measurement of dopamine transmission in the living human brain.Over the past few years, several groups have provided evidence that competition between neurotransmitters and radioligands for neuroreceptor binding allows measuring changes in synaptic neurotransmitter levels with in vivo binding techniques. In rodents, decreased uptake of D2 radioligands has been measured following amphetamine and other dopamine enhancing drugs, whereas the opposite effect (i.e., increased tracer accumulation) has been induced by drugs that decrease dopamine concentration (15)(16)(17). In baboons, decreased specific uptake of positron emission to...

Elecsys CSF biomarker assays may provide reliable alternatives to PET in Alzheimer's disease diagnosis.

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