NMDA receptor antagonists acting at the glycine B site in rat models for antipsychotic-like activity

Abstract

Several partial agonist and full antagonists acting at the glycine site of the NMDA receptors were tested for potential antipsychotic-like properties in rats. As models, amphetamine- and phencyclidine (PCP)-induced locomotor activation in the open field and PCP-induced impairment of prepulse inhibition of the acoustic startle response were employed. In the open field test, partial agonists, D-cycloserine failed to show any effect, aminocyclopropane carboxylic acid (ACPC) enhanced the action of PCP (but not that of amphetamine) and R(+)HA-966 attenuated the locomotor activation produced by both amphetamine and PCP. Both full glycineB antagonists, L-701,324 and MRZ 2/576 attenuated the action of amphetamine and PCP but at the doses that also produce transient behavioural inhibition in naive animals. A competitive NMDA receptor antagonist CGP 39551 was ineffective. In the prepulse inhibition test neither L-701,324 nor MRZ 2/576 changed sensorimotor gating in naive animals nor attenuated the disrupting effects of PCP. The present data do not support antipsychotic profile of glycineB full antagonists. However, psychotomimetic potential of glycineB antagonists seems to be low.

Discordant behavioral effects of psychotomimetic drugs in mice with altered NMDA receptor function

“…The observation that gavestinel reverses PCP-induced deficits in PPI suggests that modulation of the GMS site in either direction, antagonism or agonism, can disrupt the in vivo effects of activity-dependent NMDAR pore blockade. The present study failed to show an effect of gavestinel on PCP-induced hyperactivity although other GMS antagonists do reverse PCP-induced locomotion (Karcz-Kubicha et al 1999; Bristow et al 1993). …”

Glycine and d-serine, but not d-cycloserine, attenuate prepulse inhibition deficits induced by NMDA receptor antagonist MK-801

“…The doses of these compounds were chosen based on previous PPI studies (Le pen et al 2003;Lipina et al 2005;Curzon andDecker 1998, Yee et al 2004), other behavioral data (Nilsson et al 1997;Karcz-Kubicha et al 1999;Javitt et al 1999;Kato et al 2001), and our preliminary data.…”

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice

“…Numerous studies have shown that enhancing NMDAR function, via activation of glycine binding site or modulation of metabotropic glutamate receptors, represents a promising approach to reverse psychotomimetic effects of ketamine (Chan et al, 2008;Krystal et al, 2005;Roberts et al, 2010;Yang et al, 2010) or other NMDAR antagonists (Kanahara et al, 2008;Kawaura et al, 2015;Le Pen et al, 2003;Lipina et al, 2005;Santini et al, 2014;Shimazaki et al, 2010). On the other hand, facilitation of NMDAR-mediated transmission via direct activation of NMDAR glycine site or inhibition of the glycine transporter 1, such as GLYX-13, D-cycloserine, and sarcosine, has shown potential benefits in treatment of major depression (Burgdorf et al, 2013;Huang et al, 2013;Karcz-Kubicha et al, 1999;Papp and Moryl, 1996). Modulation of NMDAR glycine binding site has been proposed as the next wave of drug development for schizophrenia (Chang et al, 2014), depression (Dutta et al, 2015), and autism spectrum disorders (Santini et al, 2014).…”