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The cognitive effects of modulating the glycine site of the NMDA receptor with high-dose glycine in healthy controls
Abstract and Figures
N-methyl-D-aspartate (NMDA) receptors play an important role in learning and memory. Targeting the glycine modulatory site of the NMDA receptor has been suggested as a therapeutic strategy to improve cognition, although findings have not been convincing. We used the Cognitive Drug Research computerised assessment system to examine the effects of high-dose glycine on a number of cognitive processes in healthy young subjects. The study was a randomised placebo controlled repeated measures design in which each subject received acute placebo or glycine (0.8 g/kg) orally, with treatment conditions separated by a 5-day washout period. No significant effects of glycine were found on measures of working memory, declarative memory, attention or perceptual processing. These findings, together with those of previous studies, cast doubt over the ability of acute high-dose glycine to improve cognitive function in healthy subjects and suggest that the optimum dose of glycine for improving cognition may vary between different populations, possibly due to differences in endogenous glycine levels and the functional status of NMDA receptors.
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... Glycine is important neurotransmitter found in CNS, spinal cord and retina and a NMDA receptor co-agonist, and extra-cellular levels of glycine are controlled in the forebrain by the glycine type-1 transporters (GlyT-1) (Castner et al., 2014). It is associated with several neurological functions including memory and behaviour (Castner et al., 2014;Palmer et al., 2008;Betz and Becke, 1988). A typical diet contains glycine that helps to regulate the physiological function, however, the human body can make this vital amino acid from other chemicals that are used for treating schizophrenia, and memory loses (https://clinicaltrials.gov/ct2/show/NCT00575848). ...
... A typical diet contains glycine that helps to regulate the physiological function, however, the human body can make this vital amino acid from other chemicals that are used for treating schizophrenia, and memory loses (https://clinicaltrials.gov/ct2/show/NCT00575848). In central nervous system, glycine has inhibitory effect (Boissiere et al., 1998) and related to memory and behaviour regulated by the signalling of NMDAreceptors (Palmer et al., 2008;Maragos et al., 1987). It has been observed that glycine acts as co-agonist at the NMDA glutamate-receptors (Palmer et al., 2008;Kemp et al., 1988) related to memory and learning (Wu et al., 1991;Borowsky et al., 1993). ...
... In central nervous system, glycine has inhibitory effect (Boissiere et al., 1998) and related to memory and behaviour regulated by the signalling of NMDAreceptors (Palmer et al., 2008;Maragos et al., 1987). It has been observed that glycine acts as co-agonist at the NMDA glutamate-receptors (Palmer et al., 2008;Kemp et al., 1988) related to memory and learning (Wu et al., 1991;Borowsky et al., 1993). To regulate and control memory and behavioral effects, NMDAR activation requires postsynaptic de-polarisation and the binding of two agonists including glycine and glutamate. ...
Glycine is an important chemical mediator of nervous system that plays a vital role in memory and other neurological functions. Therefore, the effect of glycine on these traits must be studied to understand biological mechanisms of intricate neurological system. We investigated the effect of different doses of glycine on memory and behavior using 30 albino mice models (treated and control). After two weeks of glycine dosing, we performed light and dark activity and novel-object recognition (NOR) tests to assess the cognitive traits. Brain and blood samples were taken and kept at-70°C using ultra-low temperature freezer. Neurochemical estimation of blood glycine level was estimated by high-performance liquid chromatography with electrochemical detectors (HPLC-ECD). Concentration of glycine (100, 300 and 500 mg/kg) is significantly observed (p<0.01) and it changes due to physiological variations in N-methyl-D-aspartate (NMDA) an important neurotransmitter for memory. We observed significant increase in serotonin metabolites including 5-hydroxy tryptophan (5-HT, p<0.05) and 5-hydroxy indole acetic acid (5-HIAA, p<0.001) levels. Similarly, effects were found in case of dopamine (DA, p<0.05) and its metabolites: 3, 4-Dihydroxyphenylacetic acid (DOPAC, p<0.001) and homovanillic acid (HVA, p<0.001). Histopathological investigation of brain tissues showed cellular clumps at cortical junctions at higher doses of glycine as compared to control. These findings revealed that dose dependent concentration of glycine can be useful for memory loss and behavior deficits.
... The nervous system was examined in healthy populations in eight studies [47][48][49][50][51][52][53]68]. Improved sleep quality, alertness and cognition, and decreased week, y years GeroScience fatigue and sleepiness was observed in three populations receiving 3 g/day oral administration of glycine 30 min -1 h before bedtime over 2 -4 days [47,51,53]. ...
... Higher single bolus of 0.8 g/kg body weight orally or 200 mg/kg body weight intravenously showed negative effects on sensorimotor gating and cognitive performance in healthy populations [48,50,52]. Of the eight studies in healthy populations, one reported inconclusive effects with glycine administration [68], while another reported a statistically insignificant effect [49]. ...
Functional decline of physiological systems during ageing leads to age-related diseases. Dietary glycine increases healthy lifespan in model organisms and might decrease inflammation in humans, suggesting its geroprotective potential. This review summarises the evidence of glycine administration on the characteristics of eleven physiological systems in adult humans. Databases were searched using key search terms: ‘glycine’, ‘adult’, ‘supplementation’/ ‘administration’/ ‘ingestion’/ ‘treatment’. Glycine was administered to healthy and diseased populations (18 and 34 studies) for up to 14 days and 4 months, respectively. The nervous system demonstrated the most positive effects, including improved psychiatric symptoms from longer-term glycine administration in psychiatric populations. While longer-term glycine administration improved sleep in healthy populations, these studies had small sample sizes with a high risk of bias. Larger and long-term studies with more robust study designs in healthy populations to examine the effects of glycine administration on preventing, delaying or reversing the ageing process are warranted.
... They function as a "coincidence detector" of pre-and postsynaptic activity and have crucial roles in glutamatergic neurotransmission, local rhythmic activity, and synaptic plasticity (Collingridge et al., 1988;Olney and Farber, 1995;Jensen and Lisman, 1996;Fellin et al., 2009). Thus, NMDARs are known to modulate cognition, memory, and higher-order brain functions (Moghaddam et al., 1997;Adams and Moghaddam, 1998;Palmer et al., 2008;Collingridge et al., 2013). In the last several decades, animal models of NMDAR hypofunction have been widely utilized to study the neurobiology of schizophrenia, as well as to test drugs for treating symptoms of schizophrenia. ...
The N-methyl-d-aspartate receptor (NMDAR) hypofunction hypothesis has been proposed to help understand the etiology and pathophysiology of schizophrenia. This hypothesis was based on early observations that NMDAR antagonists could induce a full range of symptoms of schizophrenia in normal human subjects. Accumulating evidence in humans and animal studies points to NMDAR hypofunctionality as a convergence point for various symptoms of schizophrenia. Here we review animal models of NMDAR hypofunction generated by pharmacological and genetic approaches, and how they relate to the pathophysiology of schizophrenia. In addition, we discuss the limitations of animal models of NMDAR hypofunction and their potential utility for therapeutic applications.
... This is likely related to individual differences in study design, small samples, and ranges in dose. [29][30][31][32] Glycine transport across the blood-brain barrier is low, but CSF levels can be influenced in a dose-dependent manner by moderateto-high doses. 33 A 2010 meta-analysis of studies with glycinergic coagonists for the treatment of schizophrenia included an analysis of the dose-response of glycine based on 10 studies for this indication. ...
Glycine and related endogenous compounds (d-serine, d-alanine, sarcosine) serve critical roles in both excitatory and inhibitory neurotransmission and are influenced by a multitude of enzymes and transporters, including glycine transporter 1 and 2 (GlyT1 and GlyT2), d-amino acid oxidase (DAAO), serine racemase (SRR), alanine-serine-cysteine transporter 1 (Asc-1), and kynurenine aminotransferase (KAT). MEDLINE, Web of Science, and PsychINFO were searched for relevant human trials of compounds. Many studies utilizing exogenous administration of small molecule agonists of the glycineB site of n-methyl-d-aspartate receptor have been studied as have a growing number of glycine transporter type 1 (GlyT1) inhibitors. The clinical effects of these compounds are reviewed as are the potential effects of newer novel compounds.
... Such conclusion is also supported by studies on direct glycine site agonists that were found to exert pro-cognitive actions in animals (Pussinen and Sirvio, 1999;Popik and Rygielska, 1999;Duffy et al., 2008). Although results of a clinical study in healthy volunteers did not reveal procognitive efficacy of such approach (Palmer et al., 2008), this is likely to be due to the poor penetration of glycine into the brain that necessitates the use of exceptionally high doses. While high doses of glycine may exert therapeutic efficacy in schizophrenia associated with reduced glycine serum concentration (Neeman et al., 2005), healthy subjects may be more sensitive to NMDAR internalization (Martina et al., 2004) and/or activation of inhibitory glycine receptors (Song et al., 2006) triggered by high glycine levels. ...
The 5-HT7 (5-hydroxytryptamine 7, serotonin 7) receptor is one of the most recently identified members of the serotonin receptor family. Pharmacological tools, including selective antagonists and, more recently, agonists, along with 5-HT7 receptor (5-HT7R) knock-out mice have revealed the involvement of this receptor in central nervous system processes. Its well-established role in controlling body temperature and regulating sleep and circadian rhythms has implicated this receptor in mood disorders. Thus, the 5-HT7R has gained much attention as a possible target for the treatment of depression. Although preclinical data support the antidepressant-like actions of 5-HT7R antagonists, their clinical efficacy has not been yet established. Other evidence has implicated the 5-HT7R in learning and memory. Preclinical findings suggest that blockade of this receptor may be beneficial against schizophrenia-like cognitive deficits. Other possible indications include nociception, epilepsy, migraine, autism spectrum disorders, and Rett Syndrome. However, the question is whether the beneficial effects may be achieved by activation or blockade of 5-HT7Rs. Hence, this review briefly summarises the recent findings on the role of 5-HT7Rs and their ligands in CNS disorders.
Treatment-resistant schizophrenia (TRS) or suboptimal response to antipsychotics affects almost 30% of schizophrenia (SCZ) patients, and it is a relevant clinical issue with significant impact on the functional outcome and on the global burden of disease. Among putative novel treatments, glycine-centered therapeutics (i.e. sarcosine, glycine itself, D-Serine, and bitopertin) have been proposed, based on a strong preclinical rationale with, however, mixed clinical results. Therefore, a better appraisal of glycine interaction with the other major players of SCZ pathophysiology and specifically in the framework of dopamine – glutamate interactions is warranted. New methodological approaches at cutting edge of technology and drug discovery have been applied to study the role of glycine in glutamate signaling, both at presynaptic and post-synaptic level and have been instrumental for unveiling the role of glycine in dopamine-glutamate interaction. Glycine is a non-essential amino acid that plays a critical role in both inhibitory and excitatory neurotransmission. In caudal areas of central nervous system (CNS), such as spinal cord and brainstem, glycine acts as a powerful inhibitory neurotransmitter through binding to its receptor, i.e. the Glycine Receptor (GlyR). However, glycine also works as a co-agonist of the N-Methyl-D-Aspartate receptor (NMDAR) in excitatory glutamatergic neurotransmission. Glycine concentration in the synaptic cleft is finely tuned by glycine transporters, i.e. GlyT1 and GlyT2, that regulate the neurotransmitter's reuptake, with the first considered a highly potential target for psychosis therapy. Reciprocal regulation of dopamine and glycine in forebrain, glycine modulation of glutamate, glycine signaling interaction with postsynaptic density proteins at glutamatergic synapse, and human genetics of glycinergic pathways in SCZ are tackled in order to highlight the exploitation of this neurotransmitters and related molecules in SCZ and TRS.
Protective effects of vitamin E (Vit E) on long term potentiation (LTP) impairment, neuronal apoptosis and increase of nitric oxide (NO) metabolites in the hippocampus of juvenile rats were examined. The rats were grouped (n=13) as: (1) control; (2) hypothyroid (Hypo) and (3) Hypo-Vit E. Propylthiouracil (PTU) was given in drinking water (0.05%) during 6 weeks. Vit E (20 mg/ kg) was daily injected (IP). To evaluate synaptic plasticity, LTP from the CA1 area of the hippocampus followed by high frequency stimulation to the ipsilateral Schafer collateral pathway was carried out. The cortical and hippocampal tissues were then removed to measure NO metabolites. The brains of 5 animals in each group were removed for apoptosis study. The hypothyroidism status decreased the slope, 10-90% slope and amplitude of field excitatory post synaptic potential (fEPSP) compared to the control group (P<0.01-P<0.001). Injection of Vit E increased the slope, 10-90% slope and amplitude of the fEPSP in the Hypo-Vit E group in comparison to the Hypo group (P<0.05-P<0.01). TUNEL positive neurons and NO metabolites were higher in the hippocampus of the Hypo rats, as compared to those in the hippocampus of the control ones (P<0.001). Treatment of the Hypo rats by Vit E decreased apoptotic neurons (P<0.01-P<0.001) and NO metabolites (P<0.001) in the hippocampus compared to the Hypo rats. The results of the present study showed that Vit E prevented the LTP impairment and neuronal apoptosis in the hippocampus of juvenile hypothyroid rats.
Glycine is the simplest amino acid in natural, widely exists in animal body, a key material for one carbon, proteins, peptides, nucleotides, porphyrins and bile salt metabolism. Glycine is not only an inhibitory neurotransmitter in the central nervous system, but also widely involved in the regulation of metabolism, antioxidation and anti-apoptosis intissues. The major objective of this article is to provide an overview of recent findings about the protective effects of glycine on cardiovascular disease caused by myocardial ischemia, hypertension and hyperglycemia.
Lead (Pb) exposure during development is associated with impaired cognitive function and long-term potentiation (LTP). Vitamin E (VE) is an antioxidant that could have protective effects against Pb intoxication. In this study, we examined the protective effects of vitamin E against Pb-induced LTP impairments. Forty-six adult male Wistar rats were randomly divided into 6 treatment groups: (1) control; (2) Pb exposure; (3) VE; (4) Pb +VE; (5) Pb exposure followed by VE 2 months after exposure; (6) VE followed by Pb exposure 1 month after treatment. Rats were exposed to Pb through daily consumption of Pb-contaminated distilled water; VE was administered by daily gavage for 3 months. After this period, the population spike (PS) amplitudes and the slopes of excitatory postsynaptic potentials (EPSPs) were measured in the dentate gyrus (DG) area of the hippocampus in adult rats in response to electrical stimulation applied to the perforant pathway in vivo. Blood samples were also collected to evaluate malondialdehyde (MDA) levels, total antioxidant capacity (TAC), and total oxidant status (TOS). Biochemical analyses demonstrated significant increases in plasma MDA and TOS levels in the Pb-exposed group compared to the control group. VE-protected groups revealed significant increases in TAC levels. Our results demonstrate that Pb decreased EPSP slopes and PS amplitudes compared to the control group, whereas VE increased these parameters compared to the control group. Co-administration of VE with Pb exposure inhibited Pb-induced effects. These findings suggest that VE via its antioxidant activity reverses Pb-induced impairments of synaptic plasticity in the DG.
Lead (Pb) is a neurotoxic metal that is widely distributed in the environment. In experimental animals, chronic exposure to this neurotoxicant resulted in impaired synaptic plasticity and cognitive function. In this study, we examined the protective effects of vitamin C (ascorbic acid) against Pb exposure-induced impairment of long-term potentiation (LTP). Forty-four adult male Wistar rats were divided into six groups and subjected to the following treatments for three months: (1) vehicle (distilled water); (2) Pb; (3) ascorbic acid; (4) Pb+ascorbic acid; (5) Pb (two months) followed by ascorbic acid; and (6) ascorbic acid (one month) followed by Pb. After treatment, the population spike(PS) amplitude and slope of excitatory postsynaptic potentials(EPSP) were measured in the dentate gyrus(DG) of rats in vivo. Following these measurements, blood samples were collected for the following biochemical assays: malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS). There was a significant increase in plasma MDA and TOS in the Pb-intoxicated group compared to the control group. There was a significant increase in TAC levels in the ascorbic acid group. Our results also show that Pb exposure caused a decrease in the EPSP slope and PS amplitude when compared with the control group, whereas vitamin C increased these parameters. Co-administration of Pb with vitamin C inhibited the effects of Pb. These findings suggested that Pb exposure caused impairment in LTP, that may have been mediated through oxidative damage. Vitamin C ameliorated the Pb-induced impairment of synaptic plasticity in the DG via antioxidant activity.
Copyright © 2015. Published by Elsevier Inc.
N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are reported to induce schizophrenia-like symptoms in humans, including cognitive impairments. Shortcomings of most previous investigations include failure to maintain steady-state infusion conditions, test multiple doses and/or measure antagonist plasma concentrations. This double-blind, placebo-controlled, randomized, within-subjects comparison of three fixed subanesthetic, steady-state doses of intravenous ketamine in healthy males (n = 15) demonstrated dose-dependent increases in Brief Psychiatric Rating Scale positive (F[3,42] = 21.84; p < 0.0001) and negative symptoms (F[3,42] = 2.89; p = 0.047), and Scale for the Assessment of Negative Symptoms (SANS) total scores (F[3,42] = 10.55; p < 0.0001). Ketamine also produced a robust dose-dependent decrease in verbal declarative memory performance (F[3,41] = 5.11; p = 0.004), and preliminary evidence for a similar dose-dependent decrease in nonverbal declarative memory, occurring at or below plasma concentrations producing other symptoms. Increasing NMDA receptor hypofunction is associated with early occurring memory impairments followed by other schizophrenia-like symptoms.
Effects of subanesthetic doses of ketamine (0.25 and 0.5 mg/kg) on memory, cognition, psychomotor function, subjective moods, and incidence of adverse reactions were investigated in 34 healthy young volunteers. The drug caused impairment of immediate and delayed recall. Most of the impairment was due to interference with retrieval processes. Recovery was virtually complete 60 minutes after administration. The incidence of adverse reactions was high. Benzodiazepines need to be administered even when ketamine is used in subanesthetic doses. (C) Williams & Wilkins 1985. All Rights Reserved.
Background:
To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N-methyl-D-aspartate subtype of excitatory amino acid receptor.Methods:
Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured.Results:
Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure.Conclusions:
These data indicate that N-methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
A rapidly growing body of preclinical data has implicated the glutamatergic N-methyl-d-aspartate (NMDA) receptor in memory and other cognitive processes. There is comparatively less information about this receptor system in human cognition. We examined the effects of subanesthetic doses of ketamine, a noncompetitive NMDA receptor antagonist, on two forms of memory, free recall and recognition, as well as attention and behavior in a double-blind, placebo-controlled, 1-hour infusion in 15 healthy volunteers. Ketamine produced decrements in free recall, recognition memory, and attention. In addition, ketamine induced a brief psychosis in our healthy volunteers marked by thought disorder and withdrawal-retardation. Ketamine-induced memory impairments were not accounted for by changes in subject's attention and were not significantly related to psychosis ratings. These data suggest that the NMDA receptor plays a direct role in two types of explicit memory. The implications of these data for the pathophysiology of schizophrenia are discussed.
The present report considers alternative measures of sensitivity and response bias for the discrimination learning paradigm. The classical signal detection measures, d′ and β, were compared with their nonparametric equivalents, A′ and B″, with theoretical measures derived from threshold theory and with empirical measures derived from the ROC graph. Differential rabbit eyelid conditioning data from three experiments were analyzed with these measures, and the results of these analyses were used along with other information to determine which measures of sensitivity and response bias are most useful for the analysis of discrimination learning data.