D-amino acid oxidase is expressed in the ventral tegmental area and modulates cortical dopamine

Abstract

D-amino acid oxidase (DAO, DAAO) degrades the NMDA receptor co-agonist D-serine, modulating D-serine levels and thence NMDA receptor function. DAO inhibitors are under development as a therapy for schizophrenia, a disorder involving both NMDA receptor and dopaminergic dysfunction. However, a direct role for DAO in dopamine regulation has not been demonstrated. Here, we address this question in two ways. First, using in situ hybridization and immunohistochemistry, we show that DAO mRNA and immunoreactivity are present in the ventral tegmental area (VTA) of the rat, in tyrosine hydroxylase (TH)-positive and -negative neurons, and in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Second, we show that injection into the VTA of sodium benzoate, a DAO inhibitor, increases frontal cortex extracellular dopamine, as measured by in vivo microdialysis and high performance liquid chromatography. Combining sodium benzoate and D-serine did not enhance this effect, and injection of D-serine alone affected dopamine metabolites but not dopamine. These data show that DAO is expressed in the VTA, and suggest that it impacts on the mesocortical dopamine system. The mechanism by which the observed effects occur, and the implications of these findings for schizophrenia therapy, require further study.

d‐amino acid oxidase knockout (Dao−/−) mice show enhanced short‐term memory performance and heightened anxiety, but no sleep or circadian rhythm disruption

“…It is known that Dao is expressed in the ventral tegmental area (Betts et al ., ), while a recent study observed increased burst‐firing of ventral tegmental area dopaminergic neurons in Dao −/− mice (Schweimer et al ., ). Altered dopaminergic function in the ventral tegmental area might contribute to the enhanced recognition memory performance of Dao −/− mice, given that a recent in vivo calcium imaging study found that the activity of dopaminergic ventral tegmental area neurons was predictive of object recognition memory performance in mice (Gunaydin et al ., ).…”

Evidence for limited D1 and D2 receptor coexpression and colocalization within the dorsal striatum of the neonatal mouse

“…Specificity of the A2A antibody was established as part of the proximity‐ligation assay validation by Trifilieff et al (). The antibodies used against TH and choline acetyltransferase (ChAT) are standard in the field for detecting these proteins, and their specificity has been validated elsewhere (Bhagwandin et al, ; Betts et al, )…”

Time and space profiling of NMDA receptor co‐agonist functions

“…) where it may also provide a new pathway for the synthesis of dopamine (Betts et al . ). Despite many progresses, the biochemical cascades modulating DAAO activity are still poorly defined.…”