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

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 delayinduced 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 Dserine, respectively. D-Cycloserine slightly elevated D-serine levels. Conversely, S18841 exerted no influence on glycine, Dserine, 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.

Dopaminergic neuromodulation of prefrontal cortex activity requires the NMDA receptor coagonist d -serine

“…The present study may also offer a cellular explanation for previous studies showing that D-serine plays a major role in cocaine-induced sensitization (45,46) and to studies suggesting that the novel antipsychotics cariprazine and blonaneserin strengthen cognitive functions by virtue of their attenuation of D3R activity in the PFC (47,48). In addition, there is increasing interest in the potential utility for ligands at NMDAR in the management of other disorders from autism to Alzheimer's disease (49,50).…”

Brain NMDA Receptors in Schizophrenia and Depression

“…These types of drugs include glycine itself [ 145 , 146 , 147 ], other agonists of the NMDA-glycine recognition site such as D-serine [ 148 , 149 , 150 ] and the partial agonist D-cycloserine [ 151 , 152 , 153 , 154 , 155 ], as well as inhibitors of glycine transporters, such as sarcosine ( N -methyl-glycine), which increase the synaptic availability of glycine [ 156 , 157 ]. However, although preclinical studies in rodents showed that partial glycine site agonists and glycine reuptake inhibitors exhibit comparable pro-cognitive effects with the potential for the treatment of schizophrenia [ 158 ], a double-blind, randomized clinical trial concluded that neither glycine nor D-cycloserine is a generally effective therapeutic option for treating negative symptoms or cognitive impairments [ 147 ]. As a matter of fact, most clinical trials conducted to date have failed to show efficacy of these agents for the treatment of schizophrenia [ 159 ].…”

Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior

“…Therefore, in addition to the long-established “glycine neurophysiology” via (1) binding sites on glutamate NMDA receptors 56 , and (2) its cognate receptors (GlyR) in subtelencephalic areas 57 , our findings point to the third type of mechanism, starting with tRNA Gly epitranscriptomic modification, by which glycinergic pathways could critically regulate adult brain function and complex behaviors. Pharmacological alterations in glycine function in the brain 58 have shown promise for alleviating cognitive deficits 59 and depressive symptoms in humans 60 and animal models 61 , 62 . The findings presented here broadly align with the therapeutic promise of glycinergic pathways.…”