The antidepressant effects of ketamine and the underlying mechanisms

Ketamine ◽  
2015 ◽  
pp. 264-295
Keyword(s):  
Antidepressant Effects ◽  
Underlying Mechanisms

scholarly journals Asparagus cochinchinensis extract ameliorates menopausal depression in ovariectomized rats under chronic unpredictable mild stress

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hye Ryeong Kim ◽  
Young-Ju Lee ◽  
Tae-Wan Kim ◽  
Ri-Na Lim ◽  
Dae Youn Hwang ◽  
...  
Keyword(s):  
Tricyclic Antidepressant ◽  
Ovariectomized Rats ◽  
Mild Stress ◽  
Chronic Unpredictable Mild Stress ◽  
Ovx Rats ◽  
Antidepressant Effects ◽  
Antidepressant Imipramine ◽  
Asparagus Cochinchinensis ◽  
Underlying Mechanisms ◽  
Menopausal Depression

Abstract Background Depression is a serious and common psychiatric disorder generally affecting more women than men. A woman’s risk of developing depression increases steadily with age, and higher incidence is associated with the onset of menopause. Here we evaluated the antidepressant properties of Asparagus cochinchinensis (AC) extract and investigated its underlying mechanisms in a rat menopausal depression model. Methods To model this menopausal depression, we induced a menopause-like state in rats via ovariectomy and exposed them to chronic unpredictable mild stress (CUMS) for 6 weeks, which promotes the development of depression-like symptoms. During the final 4 weeks of CUMS, rats were treated with either AC extract (1000 or 2000 mg/kg, PO), which has been reported to provide antidepressant effects, or with the tricyclic antidepressant imipramine (10 mg/kg, IP). Results We report that CUMS promotes depression-like behavior and significantly increases serum corticosterone and inflammatory cytokine levels in the serum of ovariectomized (OVX) rats. We also found that CUMS decreases the expression of brain-derived neurotrophic factor (BDNF) and its primary receptor, tropomyosin receptor kinase B (TrkB), in OVX rats, and treatment with AC extract rescues both BDNF and TrkB expression levels. Conclusion These results suggest that AC extract exerts antidepressant effects, possibly via modulation of the BDNF-TrkB pathway, in a rat model of menopausal depression.

scholarly journals M2-AChR Mediates Rapid Antidepressant-Like Effects of Scopolamine Through Activating the mTORC1-BDNF

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuang Liu ◽  
Dandan Shi ◽  
Zuoli Sun ◽  
Yi He ◽  
Jian Yang ◽  
...  
Keyword(s):  
Western Blotting ◽  
Open Field Test ◽  
Forced Swim Test ◽  
Muscarinic Acetylcholine Receptor ◽  
Cholinergic Receptor ◽  
Therapeutic Effects ◽  
Antidepressant Effects ◽  
Mtorc1 Signaling ◽  
Underlying Mechanisms

Background: Scopolamine, a non-selective muscarinic acetylcholine receptor (M1~5-AChR) antagonist, has rapid and robust antidepressant effects in humans and other species. However, which of the five M-AChRs mediates these therapeutic effects has not been fully identified. Several studies implicate M2-AChR as a potential antidepressant target of scopolamine. This study aimed to explore the role of M2-AChR in scopolamine's antidepressant-like effects and determine the underlying mechanisms.Methods: We used the classic novelty suppressed feeding test (NSFT), open field test (OFT) and forced swim test (FST) to observe antidepressant-related behaviors of normal rats, medial prefrontal cortex (mPFC) neuron silenced rats and M2-AChR knockdown rats treated with scopolamine. In a further experiment, the M2 cholinergic receptor antagonist methoctramine (MCT) was injected intracerebroventricularly into normal rats. Levels of mTORC1 and brain-derived neurotrophic factor (BDNF) in the mPFC of animals were analyzed by Western blotting.Results: Consistent with previous studies, mPFC was required for the antidepressant-like effects of scopolamine, and intracerebroventricular injection of MCT into rats could produce similar antidepressant-like effects. Use of AAV-shRNA to knock down M2-AChR in the mPFC resulted in the antidepressant-like effects of scopolamine being blunted. Furthermore, Western blotting demonstrated increased expression of mTORC1 signaling and BDNF in MCT-treated rats.Conclusion: Our results indicate that M2-AChR in the mPFC mediates the antidepressant-like effects of scopolamine by increasing the expression of BDNF and activating the mTORC1 signaling pathway.

Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex

2014 ◽  
Vol 29 (7) ◽  
pp. 419-423 ◽  
Author(s):  
W. Zhou ◽  
N. Wang ◽  
C. Yang ◽  
X.-M. Li ◽  
Z.-Q. Zhou ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Mammalian Target Of Rapamycin ◽  
Rat Hippocampus ◽  
Bdnf Expression ◽  
Prefrontal Cortical ◽  
Antidepressant Effects ◽  
Immobility Time ◽  
Underlying Mechanisms

AbstractKetamine exerts fast acting, robust, and lasting antidepressant effects in a sub-anesthetic dose, however, the underlying mechanisms are still not fully elucidated. Recent studies have suggested that ketamine's antidepressant effects are probably attributed to the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The present study aimed to observe the effects of AMPA receptor modulators on mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) expression during the procedure of ketamine exerting antidepressant effects. Therefore, we pretreated rats with NBQX, an AMPA receptor antagonist, or CX546, an AMPA receptor agonist, and subsequently observed the immobility time during the forced swimming test (FST) and the hippocampal and prefrontal cortical levels of mTOR and BDNF. The results showed ketamine decreased the immobility time of rats during the FST and increased the hippocampal and prefrontal cortical mTOR and BDNF. NBQX pretreatment significantly increased the immobility time and decreased the levels of mTOR and BDNF when compared with vehicle 1 (DMSO) pretreatment. CX546 pretreatment significantly decreased the immobility time and increased the levels of mTOR and BDNF when compared with vehicle 2 (DMSO + ethanol) pretreatment. Our results suggest ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.

scholarly journals In search of the mechanisms of ketamine’s antidepressant effects: How robust is the evidence behind the mTor activation hypothesis

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 634 ◽  
Author(s):  
Susanna Popp ◽  
Berthold Behl ◽  
Jaya Julie Joshi ◽  
Thomas A. Lanz ◽  
Michael Spedding ◽  
...  
Keyword(s):  
Information Exchange ◽  
Similar Efficacy ◽  
Published Evidence ◽  
Novel Drugs ◽  
Antidepressant Effects ◽  
Significant Research ◽  
Underlying Mechanisms ◽  
Intracellular Cascades ◽  
The One

Extensive evidence on rapid and long-lasting antidepressant effects of intravenous ketamine motivated efforts to identify underlying mechanisms that would enable development of novel drugs with similar efficacy, but improved safety and pharmacokinetic profiles. It has been suggested that the antidepressant-like action of ketamine may be mediated by the activation of mTOR-dependent intracellular cascades. Therefore, without any coordination or pre-existing agreement, research labs at AbbVie, Servier, Pfizer and Alkermes started independent experiments aiming to reproduce and extend published evidence. More than a dozen experiments conducted by these four independent teams failed to detect robust effects of ketamine on markers reported to be affected in the original study by Li et al. (2010). Thus, detection of the effects of ketamine on mTOR seem to require special conditions that are difficult to identify and establish, at least in some labs. Present results emphasize the importance of publishing detailed methods either within the paper or as supplementary material. This information is essential for follow-up studies that any significant research is likely to trigger. Further, our efforts to identify individual labs that tried to establish ketamine’s effects on mTOR highlight the need for a peer-to-peer mechanism of information exchange such as the one being developed by the ECNP Preclinical Data Forum.

scholarly journals Putative rapid-acting antidepressant nitrous oxide (“laughing gas”) evokes rebound emergence of slow EEG oscillations during which TrkB signaling is induced

2018 ◽  
Author(s):  
Samuel Kohtala ◽  
Wiebke Theilmann ◽  
Marko Rosenholm ◽  
Paula Kiuru ◽  
Salla Uusitalo ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Cortical Excitability ◽  
Glycogen Synthase ◽  
Neurotrophin Receptor ◽  
Brain State ◽  
Onset Of Action ◽  
Slow Oscillations ◽  
Laughing Gas ◽  
Antidepressant Effects ◽  
Underlying Mechanisms

AbstractElectroconvulsive therapy (ECT) remains among the most efficient antidepressants but it seldom brings immediate remedy. However, a subanesthetic dose of NMDA-R (N-methyl-D-aspartate receptor) blocker ketamine ameliorates symptoms of depression already within hours. Glutamatergic excitability and regulation of TrkB neurotrophin receptor and GSK3β (glycogen synthase kinase 3β) signaling are considered as molecular-level determinants for ketamine’s antidepressant effects. Recent clinical observations suggests that nitrous oxide (N2O, “laughing gas”), another NMDA-R blocking dissociative anesthestic, also produces rapid antidepressant effects but the underlying mechanisms remain essentially unstudied. In this animal study we show that N2O, with a clinically relevant dosing regimen, evokes an emergence of rebound slow EEG (electroencephalogram) oscillations, a phenomenon considered to predict the efficacy and onset-of-action ECT. Very similar rebound slow oscillations are induced by subanesthetic ketamine and flurothyl (a treatment analogous to ECT). These responses become best evident upon drug withdrawal, i.e. after the peak of acute pharmacological actions, when their most prominent effects on cortical excitability have subsided. Most importantly, TrkB and GSK3β signaling remain unchanged during N2O administration (ongoing NMDA-R blockade) but emerge gradually upon gas withdrawal along with increased slow EEG oscillations. Collectively these findings reveal that rapid-acting antidepressants produce cortical excitability that triggers “a brain state” dominated by ongoing slow oscillations, sedation and drowsiness during which TrkB and GSK3β signaling alterations are induced.

The limits of human performance

2008 ◽  
Vol 44 ◽  
pp. 11-26 ◽  
Author(s):  
Ralph Beneke ◽  
Dieter Böning
Keyword(s):  
Human Performance ◽  
Safety Margin ◽  
Afferent Input ◽  
Metabolic Energy ◽  
Human Organism ◽  
Mechanical Resistance ◽  
As Doping ◽  
Gene And Protein Expression ◽  
Underlying Mechanisms ◽  
Biochemical Research

Human performance, defined by mechanical resistance and distance per time, includes human, task and environmental factors, all interrelated. It requires metabolic energy provided by anaerobic and aerobic metabolic energy sources. These sources have specific limitations in the capacity and rate to provide re-phosphorylation energy, which determines individual ratios of aerobic and anaerobic metabolic power and their sustainability. In healthy athletes, limits to provide and utilize metabolic energy are multifactorial, carefully matched and include a safety margin imposed in order to protect the integrity of the human organism under maximal effort. Perception of afferent input associated with effort leads to conscious or unconscious decisions to modulate or terminate performance; however, the underlying mechanisms of cerebral control are not fully understood. The idea to move borders of performance with the help of biochemicals is two millennia old. Biochemical findings resulted in highly effective substances widely used to increase performance in daily life, during preparation for sport events and during competition, but many of them must be considered as doping and therefore illegal. Supplements and food have ergogenic potential; however, numerous concepts are controversially discussed with respect to legality and particularly evidence in terms of usefulness and risks. The effect of evidence-based nutritional strategies on adaptations in terms of gene and protein expression that occur in skeletal muscle during and after exercise training sessions is widely unknown. Biochemical research is essential for better understanding of the basic mechanisms causing fatigue and the regulation of the dynamic adaptation to physical and mental training.

Orienting and Focusing in Voluntary and Involuntary Visuospatial Attention Conditions

2010 ◽  
Vol 24 (3) ◽  
pp. 198-209 ◽  
Author(s):  
Yan Wang ◽  
Jianhui Wu ◽  
Shimin Fu ◽  
Yuejia Luo
Keyword(s):  
Gain Control ◽  
Event Related Potentials ◽  
Stimulus Onset ◽  
Orientation Discrimination ◽  
Involuntary Attention ◽  
Attention Condition ◽  
Voluntary Attention ◽  
Visual Spatial ◽  
Related Potentials ◽  
Underlying Mechanisms

In the present study, we used event-related potentials (ERPs) and behavioral measurements in a peripherally cued line-orientation discrimination task to investigate the underlying mechanisms of orienting and focusing in voluntary and involuntary attention conditions. Informative peripheral cue (75% valid) with long stimulus onset asynchrony (SOA) was used in the voluntary attention condition; uninformative peripheral cue (50% valid) with short SOA was used in the involuntary attention condition. Both orienting and focusing were affected by attention type. Results for attention orienting in the voluntary attention condition confirmed the “sensory gain control theory,” as attention enhanced the amplitude of the early ERP components, P1 and N1, without latency changes. In the involuntary attention condition, compared with invalid trials, targets in the valid trials elicited larger and later contralateral P1 components, and smaller and later contralateral N1 components. Furthermore, but only in the voluntary attention condition, targets in the valid trials elicited larger N2 and P3 components than in the invalid trials. Attention focusing in the involuntary attention condition resulted in larger P1 components elicited by targets in small-cue trials compared to large-cue trials, whereas in the voluntary attention condition, larger P1 components were elicited by targets in large-cue trials than in small-cue trials. There was no interaction between orienting and focusing. These results suggest that orienting and focusing of visual-spatial attention are deployed independently regardless of attention type. In addition, the present results provide evidence of dissociation between voluntary and involuntary attention during the same task.

Response Interference as a Mechanism Underlying Implicit Measures

2008 ◽  
Vol 24 (4) ◽  
pp. 218-225 ◽  
Author(s):  
Bertram Gawronski ◽  
Roland Deutsch ◽  
Etienne P. LeBel ◽  
Kurt R. Peters
Keyword(s):  
Task Performance ◽  
Psychological Research ◽  
Implicit Measures ◽  
Mediation Model ◽  
Response Interference ◽  
Relevant Evidence ◽  
Moderated Mediation Model ◽  
Stimulus Features ◽  
Underlying Mechanisms

Over the last decade, implicit measures of mental associations (e.g., Implicit Association Test, sequential priming) have become increasingly popular in many areas of psychological research. Even though successful applications provide preliminary support for the validity of these measures, their underlying mechanisms are still controversial. The present article addresses the role of a particular mechanism that is hypothesized to mediate the influence of activated associations on task performance in many implicit measures: response interference (RI). Based on a review of relevant evidence, we argue that RI effects in implicit measures depend on participants’ attention to association-relevant stimulus features, which in turn can influence the reliability and the construct validity of these measures. Drawing on a moderated-mediation model (MMM) of task performance in RI paradigms, we provide several suggestions on how to address these problems in research using implicit measures.

The More You Say, the Less They Hear

2015 ◽  
Vol 27 (4) ◽  
pp. 159-169 ◽  
Author(s):  
Elsbeth D. Asbeek Brusse ◽  
Marieke L. Fransen ◽  
Edith G. Smit
Keyword(s):  
Hearing Protection ◽  
Entertainment Education ◽  
Mediating Role ◽  
Attitude Measures ◽  
Underlying Mechanisms

Abstract. This study examined the effects of disclosure messages in entertainment-education (E-E) on attitudes toward hearing protection and attitude toward the source. In addition, the (mediating) role of the underlying mechanisms (i.e., transportation, identification, and counterarguing) was studied. In an experiment (N = 336), three different disclosure messages were compared with a no-disclosure condition. The results show that more explicit disclosure messages negatively affect transportation and identification and stimulate the generation of counterarguments. In addition, the more explicit disclosure messages affect both attitude measures via two of these processes (i.e., transportation and counterarguing). Less explicit disclosure messages do not have this effect. Implications of the findings are discussed.

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