Acute but not chronic activation of the NMDA-coupled glycine receptor with D-cycloserine facilitates learning and retention

Recent results show that brain glucocorticoids are involved in the dysregulation of fear memory extinction in post-traumatic stress disorder patients. The present study was aimed to elucidate the possible mechanism of glucocorticoids on the conditioned fear extinction. To achieve these goals, male SD rats, fear-potentiated startle paradigm, and Western blot were used. We found that (1) systemic administration of the synthetic glucocorticoid agonist dexamethasone (DEX) facilitated extinction of conditioned fear in a dose-dependent manner (0.05, 0.1, 0.5, or 1.0 mg/kg, i.p.); (2) systemic administration of the glutamate NMDA receptor antagonist (7)-HA966 (6.0 mg/kg, i.p.) and intra-amygdala infusion of the NMDA receptor antagonists MK801 (0.5 ng/side, bilaterally) or D,L-2-amino-5-phosphonovaleric acid (AP5, 2.0 ng/side, bilaterally) blocked the DEX facilitation effect; (3) the corticosteroid synthesis inhibitor metyrapone (25 mg/kg. s.c.) blocked extinction and this was prevented by co-administration of NMDA receptor agonist D-cycloserine (DCS, 5.0 mg/kg, i.p.); (4) co-administration of DEX and DCS in subthreshold doses provided a synergistic facilitation effect on extinction (0.2 and 5 mg/kg, respectively). Control experiments indicated that co-administration of DEX and DCS did not alter the expression of conditioned fear and the effect was not due to lasting damage to the amygdala. These results suggest that glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction.

Section: Discussionsupporting

confidence: 91%

Glutamate NMDA Receptors within the Amygdala Participate in the Modulatory Effect of Glucocorticoids on Extinction of Conditioned Fear in Rats

Yang

Chao

et al. 2006

“…A growing body of data supports the view that DCS facilitates the formation of extinction memory (Ledgerwood et al, 2003;Walker et al, 2002;Yamamoto et al, 2008); moreover, DCS facilitates learning and memory using a variety of learning paradigms in diverse animal species (Land and Riccio, 1999;Matsuoka and Aigner, 1996;Monahan et al, 1989;Pitkänen et al, 1995;Pussinen et al, 1997;Quartermain et al, 1994;Thompson et al, 1992). Our findings showed that DCS administration did not affect freezing during reactivation under the present treatment protocol as comparable levels of fear were observed between DCS-and SAL-treated animals, regardless whether animals were subjected to a threatening event before learning.…”

Section: Discussionsupporting

confidence: 75%

Previous Stress Attenuates the Susceptibility to Midazolam's Disruptive Effect on Fear Memory Reconsolidation: Influence of Pre-Reactivation D-Cycloserine Administration

Bustos

Giachero

Maldonado

et al. 2009

It is well known that, under certain boundary conditions, the retrieval of a stable consolidated memory results into a labile one. During this unstable phase, memory can be vulnerable to interference by a number of pharmacological agents, including benzodiazepines. One of the goals of this study was to evaluate the vulnerability to midazolam (MDZ) after reactivation of recent and remote contextual fear memories in animals that experienced a stressful situation before learning. Animals were subjected to a restraint session and trained in a contextual fear paradigm the following day; consolidated memories were reactivated at different times after learning and different MDZ doses (1.5, 3.0 mg/kg) were administered to rats after reactivation. Our results show that MDZ did not affect memory reconsolidation in older-than-one-day memories of stressed animals, even after the administration of a higher MDZ dose and a longer reactivation session (5 min). In contrast, MDZ was effective in blocking reconsolidation at all memory ages in unstressed animals. In addition, the current research investigated whether activating NMDA sites before reactivation promotes the destabilization of resistant memories such as those of stressed animals. We tested the influence of pre-reactivation D-cycloserine (DCS), a partial NMDA agonist, on MDZ's effect on fear memory reconsolidation in stressed animals. Our findings indicate that DCS before reactivation promotes retrieval-induced lability in resistant memory traces, as MDZ-induced memory impairment in stressed rats became evident with pre-reactivation DCS but not after pre-reactivation sterile isotonic saline.

“…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.…”

Section: Medicationmentioning

confidence: 99%

D-Cycloserine Augmentation of Exposure Therapy for Post-Traumatic Stress Disorder: A Pilot Randomized Clinical Trial

Difede

Cukor

Wyka

et al. 2013

190

135

Viewing post-traumatic stress disorder (PTSD) as a disorder of emotional learning, this study used a cognitive enhancer synergistically with virtual reality exposure (VRE) therapy 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, placebocontrolled 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 pre-treatment, following sessions 3, 6, 10, post-treatment, and at 6 months. The difference in CAPS between the VRE-DCS (n ¼ 13) and VRE-placebo (n ¼ 12) groups increased over time beginning at 6 weeks, with medium to large between-group effect sizes immediately post-treatment and 6 months later (d ¼ 0.68 and d ¼ 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 post-treatment; 69% vs 17% at 6 months). Patients in the VRE-DCS group showed earlier and greater improvement in PTSD symptoms compared with the VRE-placebo group. These results suggest a promising new treatment for PTSD.