Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine

Chen, Briana K.; Luna, Victor M.; LaGamma, Christina T; Xu, Xinjun; Deng, Shi‐Xian; Suckow, Raymond F.; Cooper, Thomas B.; Shah, Abhishek; Brachman, Rebecca A.; Mendez‐David, Indira; David, Denis J.; Gardier, Alain M.; Landry, Donald W.; Denny, Christine A.

doi:10.1038/s41386-020-0714-z

Cited by 38 publications

(46 citation statements)

References 67 publications

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“…Here, none of our females were in pro-estrus at the time of injection; but our findings suggest similarly that the prophylactic effects of ketamine to prevent the development of depressive-like behavior in the FST might be modulated by estradiol levels at the time of injection. While our interpretation of our analysis of the estrus cycle at the time of injection is limited by the small sample size, our data are informative especially as they support other recent findings showing that ovarian hormones are necessary for prophylactic ketamine to drive resilience to stress in female mice (Chen et al, 2020). This adds to the current knowledge that gonadal hormones mediate the effects of ketamine on emotional behaviors.…”

Section: Discussionsupporting

confidence: 74%

Sex Differences in the Sustained Effects of Ketamine on Resilience to Chronic Stress

Okine

Shepard

Lemanski

et al. 2020

Front. Behav. Neurosci.

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Exposure to stress is recognized to be a triggering factor in several mood disorders, including depression and anxiety. There is very little understanding of why female subjects have a significantly higher risk for these conditions than males. Recent findings in male rodents indicated that prophylactic ketamine can prevent the development of a stress-induced depressive-like phenotype, providing a pharmacological tool to study the mechanisms underlying stress resilience. Unfortunately, none of these studies incorporated female subjects, nor did they provide a mechanistic understanding of the effects of ketamine on stress resilience. Our previous work identified the prefrontal glutamatergic and parvalbumin (PV) systems as potential molecular mechanisms underlying sex differences in susceptibility to stress-induced emotional deregulations. To further address this point, we treated male and female mice with a single dose of ketamine before exposure to a chronic stress paradigm to determine whether stressresilience induced by a pre-exposure to ketamine is similar in males and females and whether modulation of the prefrontal glutamatergic and PV systems by ketamine is associated with these behavioral effects. Ketamine prevented chronic stress-induced changes in behaviors in males, which was associated with a reduction in expression of PV and the NMDA receptor NR1 subunit. Ketamine did not protect females against the effects of chronic stress and did not change significantly prefrontal gene expression. Our data highlight fundamental sex differences in the sustained effects of ketamine. They also further implicate prefrontal glutamatergic transmission and PV in resilience to chronic stress.

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Section: Discussionsupporting

confidence: 74%

Sex Differences in the Sustained Effects of Ketamine on Resilience to Chronic Stress

Okine

Shepard

Lemanski

et al. 2020

Front. Behav. Neurosci.

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“…Male rodents were predominantly used in the ketamine preclinical literature for this review ( Table 1 ), which leads to a scarcity of literature on sex differences when describing ketamine’s effects on stress and fear memory. A recent study administered prophylactic ( R,S )-ketamine (30 mg/kg, IP) and its metabolites ( 2S,6S )-hydroxynorketamine (HNK) and ( 2R,6R )-HNK (0.025-30 mg/kg, IP) one week prior to contextual fear conditioning in mice; racemic ketamine and ( 2S,6S )-HNK attenuated learned fear in male mice but not in female mice [ 19 ]. Since both men and women experience traumatic injury or other traumatic events, utilizing both sexes in ketamine research with regards to fear memory is of utmost importance.…”

Section: Future Directionsmentioning

confidence: 99%

Effects of Ketamine on Rodent Fear Memory

Choi

Berman

Zhang

et al. 2020

IJMS

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Ketamine, a multimodal anesthetic drug, has become increasingly popular in the treatment of pain following traumatic injury as well as treatment-resistant major depressive disorders. However, the psychological impact of this dissociative medication on the development of stress-related disorders such as post-traumatic stress disorder (PTSD) remains controversial. To address these concerns, preclinical studies have investigated the effects of ketamine administration on fear memory and stress-related behaviors in laboratory animals. Despite a well-documented line of research examining the effects of ketamine on fear memory, there is a lack of literature reviews on this important topic. Therefore, this review article summarizes the current preclinical literature on ketamine and fear memory with a particular emphasis on the route, dose, and timing of ketamine administration in rodent fear conditioning studies. Additionally, this review describes the molecular mechanisms by which ketamine may impact fear memory and stress-related behaviors. Overall, findings from previous studies are inconsistent in that fear memory may be increased, decreased, or unaltered following ketamine administration in rodents. These conflicting results can be explained by factors such as the route, dose, and timing of ketamine administration; the interaction between ketamine and stress; and individual variability in the rodent response to ketamine. This review also recommends that future preclinical studies utilize a clinically relevant route of administration and account for biological sex differences to improve translation between preclinical and clinical investigations.

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“…Despite these promising data, it is still unknown if FENM can exhibit antidepressant and fear-attenuating properties in females. We and others have previously shown that both antidepressant and prophylactic drugs may be efficacious at different doses in male and female preclinical models ( Franceschelli et al, 2015 ; Chen et al, 2020b ). Additionally, we have also shown that prophylactic compounds that attenuate learned fear in male mice, such as ( R,S )-ketamine, (2 S ,6 S )-hydroxynorketamine, an ( R,S )-ketamine metabolite, and RS-67,333, a type IV serotonin receptor agonist, fail to alter fear learning or expression in female mice ( Chen et al, 2020a , 2020b ).…”

Section: Discussionmentioning

confidence: 95%

“…Moreover, intranasal ( S )-ketamine (Spravato), a stereospecific derivative of ( R,S )-ketamine that specifically targets NMDARs, was recently approved by the FDA as an adjunctive treatment for treatment-resistant depression and has shown strong, rapid efficacy for reducing symptoms of depression, including suicidality ( Daly et al, 2018 , 2019 ; Fedgchin et al, 2019 ; Popova et al, 2019 ; Fu et al, 2020 ; Ionescu et al, 2020 ; Nijs et al, 2020 ; Perez-Ruixo et al, 2020 ; Saad et al, 2020 ; Wajs et al, 2020 ; ClinicalTrials.gov, NCT0260929, NCT02094378, NCT02133001, NCT02343289, NCT02345148, NCT02606084, NCT02611505, NCT02674295, NCT02857777, NCT03298906). Previous studies have also shown that ( R,S )-ketamine–induced NMDAR inhibition may also prevent stress-induced behavioral despair as well as attenuate learned fear when administered prior to stress ( Amat et al, 2016 ; Brachman et al, 2016 ; McGowan et al, 2017 ; Dolzani et al, 2018 ; Mastrodonato et al, 2018 ; Pham et al, 2018 ; Chen et al, 2020b ). Despite these promising studies, ( R,S )-ketamine presents a challenge for clinical development because of its nonspecific side effects, including psychotropic actions and high abuse potential.…”

Section: Introductionmentioning

confidence: 97%

Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits

Chen

Pen

Eckmier

et al. 2021

International Journal of Neuropsychopharmacology

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Background Memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been approved for use in Alzheimer’s disease (AD), but increasing studies have investigated its utility for neuropsychiatric disorders. Here, we characterized a novel compound, fluoroethylnormemtantine (FENM), which was derived from memantine with an extra Fluor in an optimized position for in vivo biomarker labeling. We sought to determine if FENM produced similar behavioral effects as memantine and/or if FENM has beneficial effects against fear, avoidance, and behavioral despair. Methods We administered saline, FENM, or memantine prior to a number of behavioral assays, including paired-pulse inhibition (PPI), open field (OF), light dark test (LDT), forced swim test (FST), and cued fear conditioning (FC) in male Wistar rats. Results Unlike memantine, FENM did not produce nonspecific side effects and did not alter sensorimotor gating or locomotion. FENM decreased immobility in the FST. Moreover, FENM robustly facilitated fear extinction learning when administered prior to either cued FC training or tone re-exposure. Conclusions These results suggest that FENM is a promising, novel compound that robustly reduces fear behavior and may be useful for further preclinical testing.

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Sex-specific neurobiological actions of prophylactic (R,S)-ketamine, (2R,6R)-hydroxynorketamine, and (2S,6S)-hydroxynorketamine

Cited by 38 publications

References 67 publications

Sex Differences in the Sustained Effects of Ketamine on Resilience to Chronic Stress

Sex Differences in the Sustained Effects of Ketamine on Resilience to Chronic Stress

Effects of Ketamine on Rodent Fear Memory

Fluoroethylnormemantine, A Novel Derivative of Memantine, Facilitates Extinction Learning Without Sensorimotor Deficits

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