Abstract
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.
Highlights
The role of glutamatergic dysfunction in psychiatric disorders is well established, and N-methyl-D-aspartate (NMDA) receptors retain special interest because of their broad cortical and subcortical distribution, localisation on GABAergic interneurons and pyramidal cells, and key role in regulation of neuroplasticity, cognition, epilepsy, mood and motor behaviour
S18841 (3-Hydroxy-4-imidazolidinone), glycine, D-serine, D-cycloserine, sarcosine and ORG24598 were dissolved in 0.9% (w/v) saline, pH normalized where appropriate and injected in a volume of 1 ml/kg s.c. 30 min prior to each task except for glycine which was dosed at a volume of 4 ml/kg
All drugs dose-dependently prevented scopolamine-induced impairment of social recognition in adult rats and over similar dose-ranges attenuated a timedelay-induced reduction of novel object recognition (NOR) (Table 2)
Summary
The role of glutamatergic dysfunction in psychiatric disorders is well established, and N-methyl-D-aspartate (NMDA) receptors retain special interest because of their broad cortical and subcortical distribution, localisation on GABAergic interneurons and pyramidal cells, and key role in regulation of neuroplasticity, cognition, epilepsy, mood and motor behaviour. S18841 [15], was not developed clinically, this glycine site partial agonist is a very useful ligand for exploitation in parallel with the prototypical partial agonist D-cycloserine to identify the functional roles of the glycine modulatory site and ascertain underlying potentially beneficial therapeutic mechanisms. This approach was supported by the current findings that unlike other agents tested, S18841 did not significantly elevate microdialysate glycine levels making it a informative agent to examine the impact of partial agonism at the glycine site on cognitive function
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