Modulation of NMDA receptor function by inhibition of d-amino acid oxidase in rodent brain

Strick, Christine A.; Li, Cheryl; Scott, Liam; Harvey, Brian D.; Hajós, Mihály; Steyn, Stefanus J.; Piotrowski, Mary; James, Larry C.; Downs, James T.; Rago, Brian; Becker, Stacey L.; El‐Kattan, Ayman; Xu, Youfen; Ganong, Alan H.; Tingley, F. David; Ramirez, Andres D.; Seymour, Patricia A.; Guanowsky, Victor; Majchrzak, Mark J.; Fox, Carol B.; Schmidt, Christopher J.; Duplantier, Allen J.

doi:10.1016/j.neuropharm.2011.06.029

Cited by 37 publications

(36 citation statements)

References 42 publications

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“…Sodium benzoate inhibits local DAO, decreasing D-serine degradation and thereby increasing extracellular D-serine concentrations; the increased co-agonist availability enhances NMDAR signaling, with a resulting increase in dopamine neuron firing and thence dopamine release. This explanation is consistent with the known metabolism of D-serine by DAO (Almond et al, 2006; Adage et al, 2008; Duplantier et al, 2009; Strick et al, 2011), the effects of D-serine on NMDA receptor function (Schell et al, 1997; Mothet et al, 2000; Stevens et al, 2003; Panatier et al, 2006; Fossat et al, 2012; Papouin et al, 2012), and the regulation of dopamine neuron firing and release by NMDA receptors. That is, activation of VTA NMDA receptors enhances dopamine neuron burst firing (Seutin et al, 1990; Chergui et al, 1993; Wang and French, 1993) and stimulates cortical dopamine release (Kalivas et al, 1989; Takahata and Moghaddam, 1998; Westerink et al, 1998).…”

Section: Discussionsupporting

confidence: 86%

“…Its relevance for neurobiology emerged when one of its substrates, D-serine, was shown to be synthesized endogenously in brain, and to be a major co-agonist at the NMDA receptor (Schell et al, 1995; Wolosker et al, 1999; Mothet et al, 2000). Subsequent work has highlighted the roles of D-serine and its importance for brain function and dysfunction (Schell et al, 1997; Stevens et al, 2003; Yang et al, 2003; Shleper et al, 2005; Panatier et al, 2006; Strick et al, 2011; Fossat et al, 2012; Papouin et al, 2012; Gustafson et al, 2013; for review, see Wolosker et al, 2008; Oliet and Mothet, 2009; Van Horn et al, 2013), and it has become clear that DAO activity is a determinant of D-serine levels (Almond et al, 2006; Adage et al, 2008; Duplantier et al, 2009; Strick et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

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

Betts

Schweimer

Burnham

et al. 2014

Front. Synaptic Neurosci.

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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

Betts

Schweimer

Burnham

et al. 2014

Front. Synaptic Neurosci.

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“…In the present study, total brain cortex D-serine was measured. Strick et al (45) also did not see an increase in forebrain D-serine other than cerebellum, after DAAO inhibition (Compound 1) in CD-1 mice. With a longer exposure to CBIO in the drinking water (3 days), mouse plasma and kidney D-serine were elevated, but not brain D-serine (Table 2).…”

Section: Discussionmentioning

confidence: 92%

“…It is possible that mouse strain differences also exist (CD-1 mouse and C57Bl/6 in present study), and that elevations of brain D-serine from acute inhibition of DAAO are only modest. DAAO may also play less a role in modulating cortical D-serine level than serine racemase (45). With a different DAAO inhibitor (AS057278), brain D-serine only showed a modest increase and not enough to produce behavioral effects in the test employed in that study (amphetamine-induced locomotor activity) (47).…”

Section: Discussionmentioning

confidence: 99%

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

et al. 2016

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Deficits in N-methyl-D-aspartate receptor (NMDAR) function are increasingly linked to persistent negative symptoms and cognitive deficits in schizophrenia. Accordingly, clinical studies have been targeting the modulatory site of the NMDA receptor, based on the decreased function of NMDA receptor, to see whether increasing NMDA function can potentially help treat the negative and cognitive deficits seen in the disease. Glycine and D-serine are endogenous ligands to the NMDA modulatory site, but since high doses are needed to affect brain levels, related compounds are being developed, for example glycine transport (GlyT) inhibitors to potentially elevate brain glycine or targeting enzymes, such as D-amino acid oxidase (DAAO) to slow the breakdown and increase the brain level of D-serine. In the present study we further evaluated the effect of DAAO inhibitors 5-chloro-benzo[d]isoxazol-3-ol (CBIO) and sodium benzoate (NaB) in a phencyclidine (PCP) rodent mouse model to see if the inhibitors affect PCP-induced locomotor activity, alter brain D-serine level, and thereby potentially enhance D-serine responses. D-Serine dose-dependently reduced the PCP-induced locomotor activity at doses above 1000 mg/kg. Acute CBIO (30 mg/kg) did not affect PCP-induced locomotor activity, but appeared to reduce locomotor activity when given with D-serine (600 mg/kg); a dose that by itself did not have an effect. However, the effect was also present when the vehicle (Trappsol®) was tested with D-serine, suggesting that the reduction in locomotor activity was not related to DAAO inhibition, but possibly reflected enhanced bioavailability of D-serine across the blood brain barrier related to the vehicle. With this acute dose of CBIO, D-serine level in brain and plasma were not increased. Another weaker DAAO inhibitor sodium benzoate (NaB) (400 mg/kg), and NaB plus D-serine also significantly reduced PCP-induced locomotor activity, but without affecting plasma or brain D-serine level, arguing against a DAAO-mediated effect. However, NaB reduced plasma L-serine and based on reports that NaB also elevates various plasma metabolites, for example aminoisobutyric acid (AIB), a potential effect via the System A amino acid carrier may be involved in the regulation of synaptic glycine level to modulate NMDAR function needs to be investigated. Acute ascorbic acid (300 mg/kg) also inhibited PCP-induced locomotor activity, which was further attenuated in the presence of D-serine (600 mg/kg). Ascorbic acid may have an action at the dopamine membrane carrier and/or altering redox mechanisms that modulate NMDARs, but this needs to be further investigated. The findings support an effect of D-serine on PCP-induced hyperactivity. They also offer suggestions on an interaction of NaB via an unknown mechanism, other than DAAO inhibition, perhaps through metabolomic changes, and find unexpected synergy between D-serine and ascorbic acid that supports combined NMDA glycine- and redox-site intervention. Although mechanisms of these specific agents need to be det...

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“…Increases in cerebellum D-serine concentrations have also been reported after cerebellar DAAO activity was inhibited by RNAi (Burnet et al, 2011). Therefore, cerebellum tissue has been used as an indicator of central DAAO inhibition (Sparey et al, 2008;Duplantier et al, 2009;Strick et al, 2011). DAAO also has been reported to be expressed in the spinal cord of rats (Kappor and Kapoor, 1997), with localization including the dorsal horn.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Effects of a d-Amino Acid Oxidase Inhibitor Indicate a Spinal Site of Action in Rat Models of Neuropathic Pain

Hopkins

Zhao

Bowen

et al. 2013

J Pharmacol Exp Ther

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Inhibition of D-amino acid oxidase (DAAO) activity is a potential target for the treatment of chronic pain. Here we characterized the effects of systemic administration of the DAAO inhibitor 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) in rat models of neuropathic and inflammatory pain. Oral administration of SUN dose dependently attenuated tactile allodynia induced by ligation of the L5 spinal nerve (SNL) and similarly reversed thermal hyperalgesia produced by chronic constriction injury. In addition, SUN was efficacious against complete Freund's adjuvant-induced thermal hyperalgesia. In these models, maximal reversal of pain-related behaviors corresponded with maximum rates of increase in brain and plasma D-serine concentrations, indicative of full inhibition of DAAO activity. To investigate the possible site(s) of action, we recorded spontaneous nerve activity and mechanically evoked responses of central spinal cord dorsal horn neurons and compared these with spontaneous activity of peripheral dorsal root filaments in anesthetized SNL model animals. Oral SUN reduced spontaneous activity in both central and peripheral recordings at doses and pretreatment times that corresponded to reduced mechanical allodynia in behavioral experiments. After intravenous administration of SUN, the onset of action for this central effect was rapid (maximal effects within 30 minutes), but was abolished by severing afferent inputs to the dorsal horn. Overall, these results indicate that inhibition of DAAO in peripheral afferent spinal circuits reduced spontaneous neuronal activity to attenuate painrelated behaviors in rat models of neuropathic and inflammatory pain.

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Modulation of NMDA receptor function by inhibition of d-amino acid oxidase in rodent brain

Cited by 37 publications

References 42 publications

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

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

Modulating NMDA Receptor Function with d-Amino Acid Oxidase Inhibitors: Understanding Functional Activity in PCP-Treated Mouse Model

Pharmacodynamic Effects of a d-Amino Acid Oxidase Inhibitor Indicate a Spinal Site of Action in Rat Models of Neuropathic Pain

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