Behavioral and cognitive effects of the N-methyl-d-aspartate receptor co-agonist d-serine in healthy humans: Initial findings

Levin, Raz; Dor-Abarbanel, Adi Ein; Edelman, Shany; Durrant, Andrea R.; Hashimoto, Kenji; Javitt, Daniel C.; Heresco-Levy, Uriel

doi:10.1016/j.jpsychires.2014.12.007

Cited by 54 publications

(40 citation statements)

References 60 publications

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“…In rodents, N-methyl-D-aspartate receptors (NMDARs) are known to be crucial for induction of theta burst-driven LTP in the hippocampus [39] and iTBS after-effects in the neocortex [40] as well as for behavioral measures of working memory [41] and learning and memory [42]. Similarly, in humans, iTBS after-effects, working memory and RAVLT performance have all been shown to be NMDAR-dependent [15, 17, 43–45]. Thus, the relationship of reduced verbal learning and working memory to altered LTP-like plasticity in the present study may reflect a T2DM-associated brain-wide reduction in the density or efficacy of NMDARs.…”

Section: Discussionmentioning

confidence: 99%

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

Fried

Schilberg

Brem

et al. 2016

JAD

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Background Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer’s disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. Objective Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. Methods A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. Results In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. Conclusion Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions.

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Section: Discussionmentioning

confidence: 99%

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

Fried

Schilberg

Brem

et al. 2016

JAD

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“…In particular, co-agonists of the GluN1 subunit (GLYX13, D-serine) have been shown to improve mood in healthy volunteers, and reduce indices of behavioral despair in rodent behavioral tasks such as the forced-swim test (FST) and the learned helplessness (LH) paradigm (Malkesman et al, 2012; Burgdorf et al, 2013; Levin et al, 2015). In the FST, animals administered with the NMDAR co-agonists exhibited reduced immobility (despondency) in water, which indicated an antidepressant-like effect.…”

Section: Nmdar Agonists: Molecular Mechanismsmentioning

confidence: 99%

“…However, this does not account for the actions of D-serine, an endogenous co-agonist of the GluN1 subunit that does not act as an antagonist at high doses (Kleckner and Dingledine, 1988; Berger et al, 1998; Mothet et al, 2000). Unlike DCS, sarcosine, and GLYX13, D-serine has a higher affinity than glycine for the NMDAR glycine site and does not bind to other targets (Matsui et al, 1995; Levin et al, 2015). Nevertheless, D-serine has been shown to have antidepressant effects.…”

Section: “Full” Co-agonistsmentioning

confidence: 99%

“…An acute dose of D-serine reduced feelings of anxiety and sadness and improved cognitive scores in healthy volunteers (Levin et al, 2015). Likewise, in rodents, an acute dose of D-serine led to improvements in the FST, female urine sniffing test (FUST), and LH paradigm, similar to the antidepressant effects observed after a single dose of ketamine (Malkesman et al, 2012).…”

Section: “Full” Co-agonistsmentioning

confidence: 99%

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ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression

Chan

Matthews

Burnet

2017

Front. Mol. Neurosci.

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Since the discovery that a single dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, had rapid and long-lasting antidepressant effects, there has been increased interest in using NMDAR modulators in the pharmacotherapy of depression. Ketamine’s efficacy seems to imply that depression is a disorder of NMDAR hyperfunctionality. However, studies showing that not all NMDAR antagonists are able to act as antidepressants challenge this notion. Furthermore, NMDAR co-agonists have also been gaining attention as possible treatments. Co-agonists such as D-serine and sarcosine have shown efficacy in both pre-clinical models and human trials. This raises the question of how both NMDAR antagonists and agonists are able to have converging behavioral effects. Here we critically review the evidence and proposed therapeutic mechanisms for both NMDAR antagonists and agonists, and collate several theories on how both activation and inhibition of NMDARs appear to have antidepressant effects.

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“…In de groep plegers met een intellectuele disfunctie vertoont doorgaans een aanzienlijk percentage een diagnose van een psychotische stoornis [1,41], wat het belang van goede diagnostiek nogmaals onderstreept. Ook de inname van psychiatrische medicatie kan een significante wijziging in het cognitief [42] en intellectueel functioneren met zich meebrengen [43]. Bij het interpreteren van IQ-scores van een forensisch patiënt moet men dus rekening houden met mogelijke schommelingen in IQ-scores vanwege een specifieke psychische stoornis en medicatie-inname.…”

Section: Een Multidimensioneel Kader Voor Het Intellectueel Functionerenunclassified

De IQ-score in twijfel getrokken: Evolutie naar een multidimensioneel cognitief vaardigheidsprofiel

2015

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InleidingIk werk als psycholoog in de gevangenis met geïnterneerden met een verstandelijke handicap. In expertiseverslagen wordt er vaak gebruikgemaakt van SamenvattingEen foutieve of ontoereikende inschatting van het intellectueel functioneren kan verstrekkende gevolgen hebben binnen de forensische context. Niet zelden worden beschermings-en strafmaatregelen afgestemd op de intellectuele vaardigheden van de pleger. Een kwalitatieve bepaling van dit functioneren is dan ook van groot belang. Dit blijkt echter geen vanzelfsprekend gegeven te zijn. Een recente studie naar de stabiliteit van herhaalde IQ-metingen bij Vlaamse forensische patiënten (n = 176) (Habets et al., J Appl Res Intellect Disabil., 2014) geeft aan dat verschillende intelligentietesten en herhaalde metingen van eenzelfde intelligentietest niet steeds gelijkaardige resultaten opleveren. Scores verkregen op basis van intelligentietesten blijken dus niet zonder meer inwisselbaar te zijn. De huidige studie beoogt een kritische blik te werpen op de waarde van deze intelligentiemetingen en op de recente ontwikkelingen binnen dit veld. Meer specifiek worden de mogelijke oorzaken van de instabiliteit van IQscores besproken. Aansluitend worden de belangrijkste ontwikkelingen aangaande de diagnostiek van het intellectueel functioneren uiteengezet. Een gewijzigd denkkader treedt de laatste jaren immers meer en meer op de voorgrond, waarbinnen de klemtoon stelselmatig van een IQ-score naar het in kaart brengen van een breed cognitief vaardigheidsprofiel en het adaptief functioneren verschuift. Trefwoorden IQ · cognitieve vaardigheden · CHC · DSM 5 · WAIS · plegersDe IQ-score in twijfel getrokken: Evolutie naar een multidimensioneel cognitief vaardigheidsprofiel Een illustratie uit de forensische psychiatrie

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Behavioral and cognitive effects of the N-methyl-d-aspartate receptor co-agonist d-serine in healthy humans: Initial findings

Cited by 54 publications

References 60 publications

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

ON or OFF?: Modulating the N-Methyl-D-Aspartate Receptor in Major Depression

De IQ-score in twijfel getrokken: Evolutie naar een multidimensioneel cognitief vaardigheidsprofiel

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