Desensitization of the NMDA receptor complex by glycinergic ligands in cerebellar granule cell cultures.
ABSTRACT 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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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.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 11/2013; DOI:10.1038/npp.2013.317 · 8.68 Impact Factor
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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.PLoS ONE 07/2014; 9(7):e93519. DOI:10.1371/journal.pone.0093519 · 3.53 Impact Factor
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ABSTRACT: Obsessive-compulsive disorder (OCD) is a leading cause of disability, which is gaining increased recognition as evidenced by the disorder’s own category of related disorders in the DSM-5. Nonetheless, OCD remains undertreated despite the availability of well-researched and effective treatment options. Selective serotonin reuptake inhibitors (SSRIs) are a typical first-line approach, but require 4-8 weeks to become fully effective and often result in only a partial response. Underdosing is a common problem, since higher doses are usually required for OCD than for antidepressant effects. Sexual side effects are a common problem and may result in discontinuation. For partial responders, SRIs (including SSRIs and the tricyclic clomipramine) are often augmented with neuroleptics, but new research calls into question the benefits of this approach. Exposure and response/ritual prevention (Ex/RP) is a more effective method for augmenting antidepressant medications. New research indicates that Ex/RP can be made more effective by augmentation with the cognitive enhancer D-cycloserine.