Boje KM, Wong G, Skolnick P. Desensitization of the NMDA receptor complex by glycinergic ligands in cerebellar granule cell cultures. Brain Res 603: 207-214

Laboratory of Neuroscience, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
Brain Research (Impact Factor: 2.84). 02/1993; 603(2):207-14. DOI: 10.1016/0006-8993(93)91239-O
Source: PubMed


Glutamate neurotoxicity was examined in cultured cerebellar granule neurons following both prolonged (20-24 h) and brief (45 min) exposure to compounds acting at strychnine-insensitive glycine receptors. Glutamate neurotoxicity was reduced in a concentration-dependent fashion by brief exposure to the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) and the competitive antagonist, 7-chlorokynurenic acid (7-CK) with a rank order efficacy: 7-CK > HA-966 > ACPC. Neither D-cycloserine (D-CS) nor glycine affected neurotoxicity produced by maximum glutamate concentrations, while glycine but not D-CS augmented the effects of submaximum glutamate concentrations. Prolonged exposure of cultures to either full (glycine) or partial agonists (ACPC, D-CS, HA-966) abolished the neuroprotective effects of ACPC and significantly diminished the neuroprotective effects of HA-966. In contrast, the neuroprotective effects of 7-CK were only marginally reduced by prolonged exposure to glycinergic ligands, while the neuroprotection afforded by compounds acting at other loci on the NMDA receptor complex (e.g. 2-amino-5-phosphonopentanoate (APV) and dizocilpine (MK-801)) were unaltered. These effects may represent homologous desensitization of the NMDA receptor complex at its strychnine-insensitive glycine receptor induced by prolonged exposure to glycinergic agonists and partial agonists. Nonetheless, levels of the NMDA receptor subunit zeta 1 mRNA were unaffected by prolonged exposure to ACPC, indicating the apparent desensitization could involve a post-translational modification of the NMDA receptor complex.

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    • "DCS is a partial agonist and high doses may increase the antagonistic effects in NMDA receptors, decreasing the learning effects. A study with animal model suggests that the NMDA receptor can become desensitized after prolonged exposure to DCS [58]. At high doses and/or chronic administration, this substance seems to have a paradoxical antagonistic effect on the NMDA receptor [59], resulting in reduced effect of extinction of fear in animals. "
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    ABSTRACT: The treatment of anxiety is on the edge of a new era of combinations of pharmacologic and psychosocial interventions. A new wave of translational research has focused on the use of pharmacological agents as psychotherapy adjuvants using neurobiological insights into the mechanism of the action of certain psychological treatments such as exposure therapy. Recently, d-cycloserine (DCS) an antibiotic used to treat tuberculosis has been applied to enhance exposure-based treatment for anxiety and has proved to be a promising, but as yet unproven intervention. The present study aimed to evaluate the efficacy of DCS in the enhancement of exposure therapy in anxiety disorders. A systematic review/meta-analysis was conducted. Electronic searches were conducted in the databases ISI-Web of Science, Pubmed and PsycINFO. We included only randomized, double-blind, placebo-controlled trials with humans, focusing on the role of DCS in enhancing the action of exposure therapy for anxiety disorders. We identified 328 references, 13 studies were included in our final sample: 4 on obsessive-compulsive disorder, 2 on panic disorder, 2 on social anxiety disorder, 2 on posttraumatic stress disorder, one on acrophobia, and 2 on snake phobia. The results of the present meta-analysis show that DCS enhances exposure therapy in the treatment of anxiety disorders (Cohen d = -0.34; CI: -0.54 to -0.14), facilitating the specific process of extinction of fear. DCS seems to be effective when administered at a time close to the exposure therapy, at low doses and a limited number of times. DCS emerges as a potential new therapeutic approach for patients with refractory anxiety disorders that are unresponsive to the conventional treatments available. When administered correctly, DCS is a promising strategy for augmentation of CBT and could reduce health care costs, drop-out rates and bring faster relief to patients.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "A side-effect questionnaire was completed at each session; no side effects were reported. We chose weekly dosing, administered 90 min before exposure sessions, as this regimen has been effective in multiple animal and human fear extinction studies (Ledgerwood et al, 2003; Ressler et al, 2004; Walker et al, 2002) and because daily, longer-term dosing appears to reduce the cognitive enhancing effects of DCS (Quartermain et al, 1994), possibly due to desensitization of the NMDA receptor over time (Boje et al, 1993). The chosen dosing regimen allowed sufficient time for the medication to be absorbed into the bloodstream and for the session to be completed while circulating levels of the medication were still high. "
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    ABSTRACT: Viewing PTSD as a disorder of emotional learning, this study used a cognitive-enhancer synergistically with virtual reality exposure therapy (VRE) for the treatment of PTSD. The main objective was to determine if a novel pharmacotherapy, D-cycloserine (DCS), enhanced the efficacy of the psychotherapy. Pre-clinical studies suggest that when fear extinction occurs during DCS administration, neuroplasticity may be enhanced. VRE therapy is a particularly promising format to test the hypothesis that DCS enhances extinction learning, as sensory fear cues are standardized across patients. In a pilot randomized, double-blind, placebo controlled trial, 100 mg of DCS or placebo was administered 90 min before each weekly VRE session, to ensure peak plasma concentrations during the sessions, in 25 patients with chronic PTSD. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Beck Depression Inventory-II and the State-Trait Anger Expression Inventory-2. Assessments occurred at: pretreatment, following sessions 3, 6, 10, posttreatment, and at six-months. The difference in CAPS between the VRE-DCS (n=13) and VRE-placebo (n=12) groups increased over time beginning at six weeks, with medium to large between-group effect sizes immediately posttreatment and six months later (d=0.68 and d=1.13, respectively). A similar pattern was observed for depression, anger expression, and sleep. PTSD remission rates were significantly greater for the VRE-DCS group (46% vs 8% at posttreatment; 69% vs 17% at six-months). Patients in the VRE-DCS group showed earlier and greater improvement in PTSD symptoms compared to the VRE-placebo group. These results suggest a promising new treatment for PTSD.Neuropsychopharmacology accepted article preview online, 12 November 2013. doi:10.1038/npp.2013.317.
    Full-text · Article · Nov 2013 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
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    • "It is further important to note that in animal studies, DCS only revealed positive effects on learning when administered in isolated (i.e., acute) dosing [48]. When administered chronically (i.e., repeatedly over an extended period of time), the NMDA receptor complex can become desensitized, leading DCS to effectively work as an NMDA antagonist [49]. Similarly, long-term exposure to all major classes of antidepressants (including selective serotonin reuptake inhibitors, tricyclics, and monoamine reuptake inhibitors) are associated with neurochemical changes at the glycine binding site of the NMDA receptor complex, altering the action of DCS [50,51]. "
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    ABSTRACT: The goal of this review is to examine the clinical studies on d-cycloserine, a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure procedures during cognitive behavioral therapy for anxiety disorders. Although cognitive behavioral therapy and anxiolytic medications are more effective than placebo for treating anxiety disorders, there is still considerable room for further improvement. Traditional combination strategies typically yield disappointing results. However, recent studies based on translational research have shown promise to augment the neural circuitry underlying fear extinction with pharmacological means. We discuss the current state of the literature, including inconsistencies of findings and issues concerning the drug mechanism, dosing, and dose timing. D-cycloserine is a promising combination strategy for cognitive behavioral therapy of anxiety disorders by augmenting extinction learning. However, there is also evidence to suggest that d-cycloserine can facilitate reconsolidation of fear memory when exposure procedures are unsuccessful.
    Full-text · Article · Jun 2013 · Biology of Mood and Anxiety Disorders
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