SUBCORTICAL DA FUNCTION IN SCHIZOPHRENIA

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The "classical" DA (DA) hypothesis of schizophrenia proposed that hyperactivity of DA transmission is responsible for the positive symptoms (hallucinations, delusions) observed in this disorder . Several studies have recently demonstrated that amphetamine-induced DA release, measured at the level of the striatum as a whole, was increased in untreated patients with schizophrenia. These findings suggested an abnormal regulation of striatal DA release in schizophrenia. Two important limitations of these previous studies are that these measurements were restricted to the striatum and to the striatum as a whole. The ligands used did not provide enough signal to noise ratio to quantify D2 receptors in extrastriatal and the cameras used did not have the resolution required to differentiate the signals from ventral and dorsal striata. Recent developments in radiochemistry and instrumentation now permit a much more detailed mapping of DA presynaptic function with PET. We recently obtained evidence that the new PET D2 receptor radiotracer, [tSF]fallypride enable reliable measurements of both striatal and extrastriatal D2 receptors, and that its binding is vulnerable to acute fluctuations in endogenous DA. Furthermore, we recently demonstrated that the PET camera ECAT EXACT HR+ provides tile resolution to Study functional subdivisions of the Striatum. In preiiminary data, we made the observation that DA transmission in schizophrenia is not elevated in the ventral striatum, as anticipated, but rather in the precommiissural dorsal caudate nucleus (preDCA), the Striatal region that processes information; flow from the dorso- lateral prefrontal cortex (DLPFC). Here, we propose to further validate the use of [18F]fallypride to detect changes in endogenous DA in striatal and extrastriatal regions in baboons (specific aim 1) and healthy controls (specific aim 2), and study amphetamine-induced DA release in the nigro-striatal system (caudate and putamen), mesolimbic system (ventral striatum,, hippocampus and amygdala) and mesoeortical system (temporal and cingulate cortices). The hypothesis is that amphetamine-induced DA release will be elevated in the preDCA and blunted in mesocorticat DA system in patients with schizophrenia. Results from this Project will inform animals models developed in Projects by Javitt, Kandel, Rayport, and will provide neurobiological insights about schizophrenia that will be important for the development of more focused therapeutic approaches.