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

Autor: Millan Mark, Kevin C. F. Fone, Rodolphe Billiras, Alain P. Gobert, Anne Dekeyne, Jean-Michel Rivet, Dorothée Sicard, David J. G. Watson
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Autism Spectrum Disorder
Microdialysis
D-serine
Pharmacology
Glycine modulatory site
chemistry.chemical_compound
0302 clinical medicine
Cognition
Receptors
Glycine
Serine
Amino Acids
Nootropic Agents
Chemistry
Glycine Agents
Social cognition
Memory
Short-Term
Neurology
NMDA receptor
Acetylcholine
medicine.drug
Sarcosine
Scopolamine
Neuroscience (miscellaneous)
Glycine
Prefrontal Cortex
Motor Activity
Partial agonist
Receptors
N-Methyl-D-Aspartate
Article
03 medical and health sciences
Cellular and Molecular Neuroscience
Neurochemical
medicine
Animals
Neurotransmitter Uptake Inhibitors
Rats
Wistar
Freezing Reaction
Cataleptic
Social Behavior
Dose-Response Relationship
Drug
Antagonist
Recognition
Psychology
Rats
030104 developmental biology
Cycloserine
Schizophrenia
Reuptake inhibitor
Cognition Disorders
030217 neurology & neurosurgery
Zdroj: Molecular Neurobiology
ISSN: 1559-1182
Popis: 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 (40–200 mg/kg) and ORG24598 (0.63–5 mg/kg), the agonists, glycine (40–800 mg/kg), and D-serine (10–160 mg/kg) and the partial agonists, S18841 (2.5 mg/kg s.c.) and D-cycloserine (2.5–40 mg/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 (20 mg/kg), and the glycine modulatory site antagonist, L701,324 (10 mg/kg). S18841 blocked deficits in NOR following microinjection into the PFC (2.5–10 μg/side) but not the striatum. Finally, in rats socially isolated from weaning (a neurodevelopmental model of schizophrenia), S18841 (2.5 and 10 mg/kg s.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. Electronic supplementary material The online version of this article (10.1007/s12035-020-01875-9) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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