Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

Fone, Kevin C.F.; Watson, David J.G.; Billiras, Rodolphe I.; Sicard, Dorothee I.; Dekeyne, Anne; Rivet, Jean-Michel; Gobert, Alain; Millan, Mark J.

Abstract

© 2020, The Author(s). Frontocortical NMDA receptors are pivotal in regulating cognition and mood, are hypofunctional in schizophrenia, and may contribute to autistic spectrum disorders. Despite extensive interest in agents potentiating activity at the co-agonist glycine modulatory site, few comparative functional studies exist. This study systematically compared the actions of the glycine reuptake inhibitors, sarcosine (40–200mg/kg) and ORG24598 (0.63–5mg/kg), the agonists, glycine (40–800mg/kg), and D-serine (10–160mg/kg) and the partial agonists, S18841 (2.5mg/kg s.c.) and D-cycloserine (2.5–40mg/kg) that all dose-dependently prevented scopolamine disruption of social recognition in adult rats. Over similar dose ranges, they also prevented a delay-induced impairment of novel object recognition (NOR). Glycine reuptake inhibitors specifically elevated glycine but not D-serine levels in rat prefrontal cortical (PFC) microdialysates, while glycine and D-serine markedly increased levels of glycine and D-serine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, D-serine, other amino acids, monamines, or acetylcholine. Reversal of NOR deficits by systemic S18841 was prevented by the NMDA receptor antagonist, CPP (20mg/kg), and the glycine modulatory site antagonist, L701,324 (10mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5–10μg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10mg/kgs.c.) reversed impairment of NOR and contextual fear-motivated learning without altering isolation-induced hyperactivity. In conclusion, despite contrasting neurochemical profiles, partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects in rats of potential relevance to treatment of schizophrenia and other brain disorders where cognitive performance is impaired.

Citation

Fone, K. C., Watson, D. J., Billiras, R. I., Sicard, D. I., Dekeyne, A., Rivet, J., …Millan, M. J. (2020). Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management. Molecular Neurobiology, 57, 2144–2166. https://doi.org/10.1007/s12035-020-01875-9

• Journal Article Type: Article
• Acceptance Date: Jan 9, 2020
• Online Publication Date: Jan 20, 2020
• Publication Date: 2020-05
• Deposit Date: Jan 27, 2020
• Publicly Available Date: Jan 27, 2020
• Journal: Molecular Neurobiology
• Print ISSN: 0893-7648
• Electronic ISSN: 1559-1182
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 57
• Pages: 2144–2166
• DOI: https://doi.org/10.1007/s12035-020-01875-9
• Keywords: Cellular and Molecular Neuroscience
• Public URL: https://nottingham-repository.worktribe.com/output/3792424
• Publisher URL: https://link.springer.com/article/10.1007%2Fs12035-020-01875-9
• Additional Information: Received: 7 August 2019; Accepted: 9 January 2020; First Online: 20 January 2020; : ; : All procedures performed in studies involving animals were performed in accordance with the ethical standards of the University of Nottinhgam, the Animals (Scientific Procedures) Act, 1986 and ARRIVE guidelines and with approval of University of Nottingham Local Ethical Committee (behavior) or EU guidelines (microdialysis).; : We declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest. The contribution to this work made by DJGW and KCFF was financially supported by Servier. MJM, AG, RB, DS, AD and J-MR are employed by Servier.