Multiple lines of evidence suggest that prefrontal D] receptor transmission is critical in modulating working memory (WM) function and might be impaired in schizophrenia. Preliminary results presented here show that the binding of the selective D1 receptor antagonist [11C]NNC 112 is upregulated in the dorso-lateral prefrontal Cortex (DLPFC) in patients with schizophrenia and that this increase is related to poor WM performances. Preliminary data also suggest that this D1 receptor upregulation might be secondary to a sustained deficit in prefrontal dopamine (DA), which, in turn, might be secondary to N-methyl-D-aspartate (NMDA) receptors hypofunction. In specific aim 1, we will extend these PET studies with [11C]NNC 112 into a new group of patients (n = 60) and matched'controls (n = 60) and assess the relationship between D1 receptor upregulation, impaired cognition and the Val allele of the catechot-O-methyltransferase (COMT) gene, a polymorphism associated with lower cortical DA availability. The finding of elevated DLPFC [11C]NNC 112BP in patients with schizophrenia contrasts with findings from two Other PET studies that used [11C]SCH23390 and reported a decrease or no change. Studies in rodents suggest that sustained DA depletion differentially affects [11C]NNC 112 and [11C]SCH 23390 in vivo binding. Thus, the conflicting clinical results might be due to the use of different radiotracers. In Specific aim 2, a subset of patients with schizophrenia (n = 12)and controls (n = 12) scanned in specifiC aim 1 will also be scanned with [11C]SCH 23390 and to clarify the relationship between [11C]NNC 112 and [11C]SCH 23390 binding in schizophrenia. In nonhuman primates, chronic administration of antipsychotics induces a marked and regionally selective downregulation of prefrontal D1 receptors, suggesting that the upregulation of DLPFC D1 receptor in schizophrenia might be corrected with treatment. In specific aim 3, patients with schizophrenia scanned at baseline in specific aim 1 will be treated with either the antipsychotic risperidone (n = 12) or a combination of risperidone and D-Serine (a agonist at the glycine site of the NMDA receptor n = 12) and rescanned with [11C]NNC 112 after one and six months of treatment, to test the following hypotheses: a) chronic risperidone treatment is associated with normalization of [11C]NNC 112 binding in the DLPFC; b) this normalization is accelerated by augmentation of risperidone by D-serine. Results from these studies will contribute to a better understanding of the pathophysiology of the illness, and might have important consequences for drug development.