Anesthetic Ketamine Impairs Rats' Recall of Previous Information

Boultadakis, Antonios; Pitsikas, Nikolaos

doi:10.1097/aln.0b013e318219524e

Cited by 24 publications

(10 citation statements)

References 35 publications

(55 reference statements)

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“…Zarate and Machado-Vieira ( 127 ) postulated that the ability of nitrous oxide to generate NO may be important in its antidepressant actions. Consistent with this, some synaptic and memory impairing effects of ketamine involve NO synthesis ( 78 , 128 ).…”

Section: Other Potential Mechanisms Of Nitrous Oxidesupporting

confidence: 54%

Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy

et al. 2015

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Major depressive disorder (MDD) remains a huge personal and societal encumbrance. Particularly burdensome is a virulent subtype of MDD, treatment resistant major depression (TMRD), which afflicts 15–30% of MDD patients. There has been recent interest in N-methyl-d-aspartate receptors (NMDARs) as targets for treatment of MDD and perhaps TMRD. To date, most pre-clinical and clinical studies have focused on ketamine, although psychotomimetic and other side effects may limit ketamine’s utility. These considerations prompted a recent promising pilot clinical trial of nitrous oxide, an NMDAR antagonist that acts through a mechanism distinct from that of ketamine, in patients with severe TRMD. In this paper, we review the clinical picture of TRMD as a subtype of MDD, the evolution of ketamine as a fast-acting antidepressant, and clinical and basic science studies supporting the possible use of nitrous oxide as a rapid antidepressant.

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Section: Other Potential Mechanisms Of Nitrous Oxidesupporting

confidence: 54%

Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy

et al. 2015

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“…Neither CSDS nor acute ketamine affected locomotor activity, an important factor to rule out non-specific effects on gross motor output that can complicate data interpretation. Considering that ketamine produces amnestic effects in rodents (52,53), we assessed the possibility that ketamine interferes with stress-related learning and memory. Consistent with previous work (50), we found that 20 mg/kg ketamine does not interfere with performance in the passive avoidance test, suggesting that the antidepressant-like effects of the drug in our studies are not due to memory impairment.…”

Section: Discussionmentioning

confidence: 99%

“…While standard antidepressant treatments have delayed therapeutic efficacy (often several weeks), recent studies demonstrate that a single dose of ketamine can produce rapid (though transient) antidepressant responses in depressed patients (31–37)—including patients that are treatment-resistant (32,34,38,39)—and antidepressant-like effects in numerous models of depression (40–51). To determine if the therapeutic-like actions of ketamine are accompanied by amnestic (learning- and memory-disrupting) effects often associated with NMDA antagonists (52,53) or anxiolytic effects (43) we examined performance in the passive-avoidance and elevated plus maze (EPM) tests. As a way of evaluating whether it is possible to mitigate the effects of CSDS on ICSS, we included studies using ΔFosB-overexpressing mice, which are less sensitive (resilient) to CSDS (54).…”

Section: Introductionmentioning

confidence: 99%

Effects of Striatal ΔFosB Overexpression and Ketamine on Social Defeat Stress–Induced Anhedonia in Mice

Donahue

Muschamp

Russo

et al. 2014

Biological Psychiatry

146

121

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Background Chronic social defeat stress (CSDS) produces persistent behavioral adaptations in mice. In many behavioral assays, it can be difficult to determine if these adaptations reflect core signs of depression. We designed studies to characterize the effects of CSDS on sensitivity to reward, since anhedonia (reduced sensitivity to reward) is a defining characteristic of depressive disorders in humans. We also examined the effects of striatal ΔFosB overexpression or the N-methyl-D-aspartate antagonist ketamine, both of which promote resilience, on CSDS-induced alterations in reward function and social interaction. Methods We used intracranial self-stimulation (ICSS) to quantify CSDS-induced changes in reward function. Mice were implanted with lateral hypothalamic (LH) electrodes and ICSS thresholds were measured following each of 10 daily CSDS sessions, and during a 5-day recovery period. We also examined if acute administration of ketamine (2.5–20 mg/kg, intraperitoneal) reverses CSDS-induced effects on reward or, in separate mice, social interaction. Results CSDS increased ICSS thresholds, indicating decreases in the rewarding impact of LH stimulation (anhedonia). This effect was attenuated in mice overexpressing ΔFosB in striatum, consistent with pro-resilient actions of this transcription factor. High but not low doses of ketamine administered after completion of the CSDS regimen attenuated social avoidance in defeated mice, although this effect was transient. Ketamine did not block CSDS-induced anhedonia in the ICSS test. Conclusions Our findings demonstrate that CSDS triggers persistent anhedonia, and confirm that ΔFosB overexpression produces stress resilience. They also indicate that acute ketamine fails to attenuate CSDS-induced anhedonia despite reducing other depression-related behavioral abnormalities.

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“…These results suggest that although there is a temporal delay between ketamine administration and LTP inhibition, ketamine-induced metaplasticity shares at least some mechanisms with the acute LTP inhibition observed following other treatments that activate NMDARs (Zorumski and Izumi, 2012). Interestingly, NOS inhibitors have also been found to overcome memory impairment (Boultadakis and Pitsikas, 2010; 2011; Wass et al, 2006) and information processing defects (Palsson et al, 2010) by ketamine and other NMDAR channel blockers, and have antidepressant effects in rodent models (Doucet et al, 2012). Whether ketamine-induced metaplasticity shares other mechanisms with acute NMDA-mediated LTP inhibition, including calcium influx, serine phosphatases and p38 mitogen activated protein kinase (Izumi et al, 1992b; Izumi et al, 2008) remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function

Izumi

Zorumski

2014

Neuropharmacology

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Ketamine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist of interest in neuropsychiatry. In the present studies, we examined the effects of subanesthetic, low micromolar ketamine on excitatory postsynaptic potentials (EPSPs), population spikes (PSs) and synaptic plasticity in the CA1 region of rat hippocampal slices. Ketamine acutely inhibited NMDAR-mediated synaptic responses with half-maximal effects near 10 µM. When administered for 15–30 min at 1–10 µM, ketamine had no effect on baseline dendritic AMPA receptor-mediated EPSPs, but persistently enhanced somatic EPSPs in the pyramidal cell body layer and augmented PS firing. Acute low micromolar ketamine also had no effect on the induction of long-term potentiation (LTP) but blocked long-term depression (LTD). Following 30 min administration of 1–10 µM ketamine, however, a slowly developing and persistent form of LTP inhibition was observed that took two hours following ketamine washout to become manifest. This LTP inhibition did not result from prolonged or enhanced NMDAR inhibition during drug washout. Effects of low ketamine on somatic EPSPs and LTP were not mimicked by a high ketamine concentration that completely inhibited NMDARs, and both of these effects were blocked by co-administration of low ketamine with a low concentration of the competitive NMDAR antagonist, 2-amino-5-phosphonovalerate or inhibitors of nitric oxide synthase. These results indicate that concentrations of ketamine relevant to psychotropic and psychotomimetic effects have complex metaplastic effects on hippocampal function that involve activation of unblocked NMDARs during ketamine exposure.

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Anesthetic Ketamine Impairs Rats' Recall of Previous Information

Cited by 24 publications

References 35 publications

Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy

Treatment-Resistant Major Depression: Rationale for NMDA Receptors as Targets and Nitrous Oxide as Therapy

Effects of Striatal ΔFosB Overexpression and Ketamine on Social Defeat Stress–Induced Anhedonia in Mice

Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function

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