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...

The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D2 receptor. We measured in vivo occupancy of striatal D 2 receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D2 receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D 2 receptor availability in patients with schizophrenia (19% ؎ 11%) compared with control subjects (9% ؎ 7%, P ‫؍‬ 0.003). The increased occupancy of D2 receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D2 receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D1 receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D1 receptor availability was measured with positron emission tomography and the selective D1 receptor antagonist [11C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [11C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 +/- 0.39 ml/gm) compared with control subjects (1.27 +/- 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [11C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D1 receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D1 receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.

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These findings suggest that schizophrenia is associated with elevated dopamine function in associative regions of the striatum. Because the precommissural dorsal caudate processes information from the dorsolateral prefrontal cortex, this observation also suggests that elevated subcortical dopamine function might adversely affect performance of the dorsolateral prefrontal cortex in schizophrenia. On the other hand, the absence of a group difference in the limbic striatum brings into question the therapeutic relevance of the mesolimbic selectivity of second-generation antipsychotic drugs.

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To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.

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