Prophylactic Ketamine Attenuates Learned Fear

McGowan, Josephine C.; LaGamma, Christina T; Lim, Sean C.; Tsitsiklis, Melina; Neria, Yuval; Brachman, Rebecca A.; Denny, Christine A.

doi:10.1038/npp.2017.19

Cited by 77 publications

(77 citation statements)

References 75 publications

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“…Here, we did not find that (R,S)-ketamine and (2R,6R)-HNK were antidepressant in female mice. However, we do not believe these results contradict previous findings (24)(25)42). Instead, differences in mouse strain and drug dosing likely contributed to the discrepancies that we have demonstrated.…”

Section: Discussioncontrasting

confidence: 99%

“…We have recently shown that a single injection of (R,S)-ketamine given 1 week prior to CFC can attenuate learned fear in male mice (25) The FST is a behavioral assay that is broadly considered to have predictive validity when quantifying antidepressant efficacy (28). On day 1 of the FST, immobility time was comparable between saline and (R,S)-ketamine mice (30 mg/kg) ( Figure S01D).…”

Section: (2r6r)-hnk and (2s6s)-hnk Protect Against Distinct Stress-mentioning

confidence: 96%

“…To determine the optimal time window of administration in female mice, we sought to determine if either compound could act prophylactically when given over a smaller time interval before stress ( Figure S06A). We previously reported that (R,S)-ketamine attenuates learned fear when administered 1 week, but not 1 day or 1 month before stress in male mice (25). Here, saline, (R,S)-ketamine (2.5 mg/kg, 10 mg/kg, and 30 mg/kg), or (2R,6R)-HNK (0.025 mg/kg) was administered 3 days, instead of 1 week, before CFC in To test if (2R,6R)-HNK could be effective at an even smaller time interval, (2R,6R)-HNK was administered 24 hours before stress.…”

Section: (Rs)-ketamine and (2r6r)-hnk Prevent Lh-induced Depressivementioning

confidence: 97%

“…These data indicate that unlike in males, (R,S)-ketamine and (2R,6R)-HNK does not alter helpless behavior, but decreases stressinduced depressive-like behavior and may be anxiolytic in females exposed to LH stress. week, but not one day or one month, before exposure to stress in male mice (29). To determine the optimal time window of administration in female mice, we sought to determine if either compound could act prophylactically when given over a smaller time interval before stress ( Figure S06A).…”

Section: (Rs)-ketamine and (2r6r)-hnk Prevent Lh-induced Depressivementioning

confidence: 99%

“…In addition to (R,S)-ketamine's actions in treating MDD, recent research indicate that (R,S)-ketamine could be used to prevent stress-induced depression before it develops. Our lab and others have shown that a single injection of (R,S)-ketamine before stress can protect against the onset of stress-induced depressive-like behavior and social avoidance as well as attenuate learned fear, suggesting the possibility of developing resilience-enhancing pharmacotherapy (24)(25)(26)(27). However, it is still unknown whether stereospecific (R,S)-ketamine metabolites can have the same prophylactic efficacy of their racemic precursor.…”

Section: Introductionmentioning

confidence: 95%

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Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

et al. 2019

Preprint

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Number of words in the abstract: 227 (250 max)Number of words in the text: 3812 (4000 max) ABSTRACT BACKGROUND: Females are more likely than males to develop major depressive disorder (MDD) after exposure to stress. We previously reported that the administration of (R,S)-ketamine before stress can prevent stress-induced depressive-like behavior in male mice but have yet to assess efficacy in female mice or for other compounds, such as the metabolites of (R,S)-ketamine. METHODS:We administered (R,S)-ketamine or its metabolites (2R,6R)hydroxynorketamine ((2R,6R)-HNK) and (2S,6S)-HNK at various doses 1 week before one of a number of stressors, including contextual fear conditioning (CFC), learned helplessness (LH), and chronic immobilization stress (CIS), in male and female 129S6/SvEv mice. To examine the interaction between ovarian hormones and stress resilience, female mice also underwent ovariectomy surgery (OVX) and a hormone replacement protocol prior to drug administration. RESULTS: (R,S)-ketamine and (2S,6S)-HNK, but not (2R,6R)-HNK, attenuated learned fear in male mice. (R,S)-ketamine and (2R,6R)-HNK, but not (2S,6S)-HNK, significantly reduced stress-induced depressive-like behavior in male and female mice. (R,S)ketamine and (2R,6R)-HNK) were prophylactically effective at a lower dose (10 mg/kg and 0.025 mg/kg, respectively) in female mice than in male mice (30 mg/kg and 0.075 mg/kg, respectively). Moreover, ovarian-derived hormones were necessary and sufficient for prophylaxis in female mice. CONCLUSIONS:Our results suggest that prophylactics against stress-induced depressive-like behavior can be developed in a sex-specific manner and that ovarian hormones mediate prophylactic efficacy in females. To our knowledge, this is the first

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Section: Discussioncontrasting

confidence: 99%

Section: (2r6r)-hnk and (2s6s)-hnk Protect Against Distinct Stress-mentioning

confidence: 96%

Section: (Rs)-ketamine and (2r6r)-hnk Prevent Lh-induced Depressivementioning

confidence: 97%

Section: (Rs)-ketamine and (2r6r)-hnk Prevent Lh-induced Depressivementioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

et al. 2019

Preprint

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Subanesthetic Dose Ketamine in Posttraumatic Stress Disorder: A Role for Reconsolidation During Trauma-Focused Psychotherapy?

Veen

Jacobs

Philippens

et al. 2018

Behavioral Neurobiology of PTSD

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Despite efforts to develop more effective therapies, PTSD remains a difficult disorder to treat. Insight into the dynamic nature of memory formation and its required molecular machinery can provide an opportunity to target pathological memories for emotionally arousing events. As memories become labile upon retrieval, novel information can update the strength and course of these consolidated memories. Targeting the process of reconsolidation may offer a relevant approach to attenuate fearful and traumatic memories. Specific molecular mechanisms that are required for reconsolidation of arousing information include an intact functioning of the glutamatergic signaling pathways and, more specifically, the integrity of NMDA receptors. Ketamine, a noncompetitive NMDA-receptor antagonist, is receiving increasing interest for a variety of psychiatric indications. This compound can also be an interesting candidate for targeting emotional memories. We explore whether single intravenous infusion of a subanesthetic dose of ketamine can be considered as a viable augmentation strategy for trauma-focused psychotherapy in patients with PTSD. As a consequence, a systematic approach is needed to assess the pharmacodynamic effects of ketamine in relation to both psychotherapy and its pharmacokinetics prior to its application in patient populations. By using a "question-based drug development plan," we can explore such aspects for novel drugs, and we formulated five additional topics that need to be addressed concerning the psychotherapeutic approach and phase orientation of pharmacological assisted psychotherapy.

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Current Glutamatergic Treatments and Future Directions for Glutamate-Based Management of Chronic Stress and Stress-Related Disorders

Coutellier

Musazzi

Pavlovic³

2022

Glutamate and Neuropsychiatric Disorders

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Prophylactic Ketamine Attenuates Learned Fear

Cited by 77 publications

References 75 publications

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

Ovarian hormones mediate the prophylactic efficacy of (R,S)-ketamine and (2R,6R)-hydroxynorketamine in female mice

Subanesthetic Dose Ketamine in Posttraumatic Stress Disorder: A Role for Reconsolidation During Trauma-Focused Psychotherapy?

Current Glutamatergic Treatments and Future Directions for Glutamate-Based Management of Chronic Stress and Stress-Related Disorders

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