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Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus

/ Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / / , , ,

Abstract

BACKGROUND AND PURPOSE: Astroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes’ morphology in a genetic animal model of depression.

EXPERIMENTAL APPROACH: S-Ketamine (15 mg·kg-1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test.

KEY RESULTS: FSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1 day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1 day following ketamine treatment.

CONCLUSIONS AND IMPLICATIONS: Our results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour.

Ardalan, M., Rafati, A. H., Nyengaard, J. R., & Wegener, G. (2017). Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus. British Journal of Pharmacology, 174(6), 483-492. 10.1111/bph.13714
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Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats

/ Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / / , , ,

Abstract

Clinical studies on the role of the glutamatergic system in the pathogenesis of depression found that ketamine induces an antidepressant response, but the molecular mechanisms remain unclear. The present study investigated the effects of sub-anesthetic doses of ketamine on the glutamate reuptake function in the rat hippocampus. Chronic unpredictable mild stress (CUMS) was applied to construct animal models of depression. Sixty adult male Sprague-Dawley rats were randomly assigned to 5 groups and received a different regimen of CUMS and ketamine (10, 25, and 50 mg/kg) treatment. The sucrose preference test and open-field test were used to assess behavioral changes. The expression levels of excitatory amino acid transporters (EAATs) were measured by western blot. Microdialysis and high-performance liquid chromatography (HPLC) were used to detect hippocampal glutamate concentrations. We found that the expression of EAAT2 and EAAT3 were obviously downregulated, and extracellular concentrations of glutamate were significantly increased in the hippocampi of depressive-like rats. Ketamine (10, 25, and 50 mg/kg) upregulated the expression of EAAT2 and EAAT3, decreased the hippocampal concentration of extracellular glutamate, and alleviated the rats’ depressive-like behavior. The antidepressant effect of ketamine may be linked to the regulation of EAAT expression and the enhancement of glutamate uptake in the hippocampus of depressive-like rats.

Zhu, X., Ye, G., Wang, Z., Luo, J., & Hao, X. (2017). Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats. Neuroscience Letters, 639, 132-137. 10.1016/j.neulet.2016.12.070
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Disrupted integration of sensory stimuli with information about the movement of the body as a mechanism explaining LSD-induced experience

/ LSD, Papers, Psychology, Publications / /

Abstract

LSD (lysergic acid diethylamide) is a model psychedelic drug used to study mechanism underlying the effects induced by hallucinogens. However, despite advanced knowledge about molecular mechanism responsible for the effects induced by LSD and other related substances acting at serotonergic 5-HT2a receptors, we still do not understand how these drugs trigger specific sensory experiences. LSD-induced experience is characterised by perception of movement in the environment and by presence of various bodily sensations such as floating in space, merging into surroundings and movement out of the physical body (the out-of-body experience). It means that a large part of the experience induced by the LSD can be simplified to the illusory movement that can be attributed to the self or to external objects. The phenomenology of the LSD-induced experience has been combined with the fact that serotonergic neurons provide all major parts of the brain with information about the level of tonic motor activity, occurrence of external stimuli and the execution of orienting responses. Therefore, it has been proposed that LSD-induced stimulation of 5-HT2a receptors disrupts the integration of the sensory stimuli with information about the movement of the body leading to perception of illusory movement.

Juszczak, G. R. (2017). Disrupted integration of sensory stimuli with information about the movement of the body as a mechanism explaining LSD-induced experience. Medical Hypotheses, 100, 94-97. 10.1016/j.mehy.2017.01.022
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Effect of a Hallucinogenic Serotonin 5-HT2A Receptor Agonist on Visually-Guided, Hippocampal-Dependent Spatial Cognition in C57BL/6J Mice

/ Neuroscience, Papers, Psychology, Publications / / , ,

Abstract

By acting on serotonin 5-HT2A receptors (5-HT2ARs), serotonergic psychedelic drugs induce perceptual and visual hallucinations by increasing neuronal excitability and altering visual-evoked neuronal responses. The present study was designed to examine whether the perceptual alterations induced by a serotonergic psychedelic drug would affect the integrity of hippocampal-dependent, visually guided spatial cognition. phenylalkylamine hallucinogen TCB-2 is a selective agonist of 5-HT2ARs. Mice received TCB-2 (1.0 mg kg−1, i.p.), and spatial behaviors and hippocampal electrophysiological responses were measured with water maze tasks and in vivosingle-unit recording, respectively. TCB-2 did not affect visual cue approach behavior in the visible platform water maze, but increased the latency of trained mice to initiate goal-directed swimming during a probe test in the hidden platform Morris water maze, which could be prevented by 5-HT2AR antagonist MDL 11,939. Interestingly, TCB-2 did not affect the efficiency of the swim path or the proper use of distal visual cues during the probe test. Hippocampal place cell activity is considered to represent spatial and context-specific episodic memory. Systemic TCB-2 did not affect previously established place fields of CA1 neurons in mice exploring a familiar environment, or the remapping of place cells when the mice explored a novel environment. However, TCB-2 impaired the long-term stability of place fields for the novel environment initially encoded under the influence of TCB-2, which could be prevented by 5-HT2AR antagonist MDL 11,939. Our data indicate that hallucinogenic 5-HT2AR agonist delays the initiation of spatial search behavior, but does not impair the use of visual cues to guide goal-directed spatial behavior. Moreover, activation of 5-HT2ARs does not impair the coding and retrieval of spatial information, but impairs the long-term stability of new formed place fields of CA1 neurons.

Zhang, G., Cinalli, D., & Stackman, R. W. (2017). Effect of a hallucinogenic serotonin 5‐HT2A receptor agonist on visually guided, hippocampal‐dependent spatial cognition in C57BL/6J mice. Hippocampus. 10.1002/hipo.22712
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Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / ,

Abstract

Objective: Depression is a common condition among patients with multiple sclerosis and often becomes resistant to oral antidepressants. We report a patient with multiple sclerosis who developed severe treatment-resistant depression and who was successfully treated with intravenous ketamine over the period of two years.
Methods: Ketamine treatment protocol included an initial series of six treatments administered every other day, followed by a maintenance schedule. Ketamine was administered intravenously at 0.5mg/kg of ideal body weight over 40 minutes. Depression symptoms were measured using Beck Depression Index.
Results: The patient’s Beck Depression Index score prior to initiating ketamine treatment was 38, corresponding to severe depression. Response to treatment, defined as 50-percent reduction in Beck Depression Index score, was observed after five treatments. For this patient, the maintenance schedule ranged from a weekly treatment to one treatment every three weeks. During the two-year observation period, this patient was able to maintain a stable non-depressed mood and had no worsening of her MS symptoms.
Conclusion: Ketamine may be an alternative treatment for resistant depression and may have a special use in patients with multiple sclerosis.
Messer, M. M., & Haller, I. V. (2017). Ketamine Therapy for Treatment-resistant Depression in a Patient with Multiple Sclerosis: A Case Report. Innovations in clinical neuroscience, 14(1-2), 56.
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Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , ,

Abstract

RATIONALE: Depression is characterized by an excessive attribution of value to negative feedback. This imbalance in feedback sensitivity can be measured using the probabilistic reversal-learning (PRL) task. This task was initially designed for clinical research, but introduction of its rodent version provides a new and much needed translational paradigm to evaluate potential novel antidepressants.

OBJECTIVES: In the present study, we aimed at evaluating the effects of a compound showing clear antidepressant properties-ketamine (KET)-on the sensitivity of rats to positive and negative feedback in the PRL paradigm.

METHODS: We trained healthy rats in an operant version of the PRL task. For successful completion of the task, subjects had to learn to ignore infrequent and misleading feedback, arising from the probabilistic (80:20) nature of the discrimination. Subsequently, we evaluated the effect of KET (5, 10, and 20 mg/kg) on feedback sensitivity 1, 24, and 48 h after administration.

RESULTS: We report that acute administration of the highest dose of KET (20 mg/kg) rapidly and persistently decreases the proportion of lose-shift responses made by rats after receiving negative feedback.

CONCLUSION: Present results suggest that KET decreases negative feedback sensitivity and that changes in this basic neurocognitive function might be one of the factors responsible for its antidepressant action.

Rychlik, M., Bollen, E., & Rygula, R. (2016). Ketamine decreases sensitivity of male rats to misleading negative feedback in a probabilistic reversal-learning task. Psychopharmacology, 1-8. 10.1007/s00213-016-4497-1
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Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance

/ Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / /

Abstract

Psilocybin and psilocin are controlled substances in many countries. These are the two main hallucinogenic compounds of the “magic mushrooms” and both act as agonists or partial agonists at 5-hydroxytryptamine (5-HT)2A subtype receptors. During the last few years, psilocybin and psilocin have gained therapeutic relevance but considerable physiological variability between individuals that can influence dose-response and toxicological profile has been reported. This review aims to discuss metabolism of psilocybin and psilocin, by presenting all major and minor psychoactive metabolites. Psilocybin is primarily a pro-drug that is dephosphorylated by alkaline phosphatase to active metabolite psilocin. This last is then further metabolized, psilocin-O-glucuronide being the main urinary metabolite with clinical and forensic relevance in diagnosis.

Dinis-Oliveira, R. J. (2016). METABOLISM OF PSILOCYBIN AND PSILOCIN: CLINICAL AND FORENSIC TOXICOLOGICAL RELEVANCE. Drug Metabolism Reviews, (just-accepted), 1-21. 10.1080/03602532.2016.1278228
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“Being with a Buddha”: A Case Report of Methoxetamine Use in a United States Veteran with PTSD

/ Anxiety Disorders / PTSD, Ketamine, Papers, Psychology / / , ,

Abstract

Methoxetamine (MXE) is a ketamine analogue with a high affinity for the N-methyl-D-aspartate (NMDA) receptor. MXE is a newly emerging designer drug of abuse and is widely available through on-line sources and is not detected by routine urine drug screens. In this report, we describe a United States (US) veteran with posttraumatic stress disorder (PTSD) and heavy polysubstance use, who injected high dose MXE for its calming effect. Given MXE’s structural similarities to ketamine and recent work showing that ketamine reduces PTSD symptoms, we hypothesize that MXE alleviated this veteran’s PTSD symptoms through action at the NMDA receptor and via influences on brain-derived neurotrophic factor (BDNF). To our knowledge, this is the first case report of self-reported use of MXE in the US veteran population. More awareness of designer drugs, such as MXE, is an important first step in engaging patients in the treatment of designer drug addiction in both military/veteran settings and civilian settings.
Striebel, J. M., Nelson, E. E., & Kalapatapu, R. K. (2017). “Being with a Buddha”: A Case Report of Methoxetamine Use in a United States Veteran with PTSD. Case reports in psychiatry, 2017. 10.1155/2017/2319094
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"Being with a Buddha": A Case Report of Methoxetamine Use in a United States Veteran with PTSD

/ Anxiety Disorders / PTSD, Ketamine, Papers, Psychology / / , ,

Abstract

Methoxetamine (MXE) is a ketamine analogue with a high affinity for the N-methyl-D-aspartate (NMDA) receptor. MXE is a newly emerging designer drug of abuse and is widely available through on-line sources and is not detected by routine urine drug screens. In this report, we describe a United States (US) veteran with posttraumatic stress disorder (PTSD) and heavy polysubstance use, who injected high dose MXE for its calming effect. Given MXE’s structural similarities to ketamine and recent work showing that ketamine reduces PTSD symptoms, we hypothesize that MXE alleviated this veteran’s PTSD symptoms through action at the NMDA receptor and via influences on brain-derived neurotrophic factor (BDNF). To our knowledge, this is the first case report of self-reported use of MXE in the US veteran population. More awareness of designer drugs, such as MXE, is an important first step in engaging patients in the treatment of designer drug addiction in both military/veteran settings and civilian settings.
Striebel, J. M., Nelson, E. E., & Kalapatapu, R. K. (2017). “Being with a Buddha”: A Case Report of Methoxetamine Use in a United States Veteran with PTSD. Case reports in psychiatry, 2017. 10.1155/2017/2319094
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Prophylactic Ketamine Attenuates Learned Fear

/ Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / / , , , , , ,

Abstract

Ketamine has been reported to be an efficacious antidepressant for major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Most recently, ketamine has also been shown to be prophylactic against stress-induced depressive-like behavior in mice. It remains unknown, however, when ketamine should be administered relative to a stressor in order to maximize its antidepressant and/or prophylactic effects. Moreover, it is unknown if ketamine can be prophylactic against subsequent stressors. We systematically administered ketamine at different time points relative to a fear experience in order to determine when ketamine is most effective at reducing fear expression or preventing fear reactivation. Using a contextual fear conditioning (CFC) paradigm, mice were administered a single dose of saline or ketamine (30 mg kg−1) at varying time points before or after CFC. Mice administered prophylactic ketamine 1 week, but not 1 month or 1 h before CFC, exhibited reduced freezing behavior when compared with mice administered saline. In contrast, ketamine administration following CFC or during extinction did not alter subsequent fear expression. However, ketamine administered before reinstatement increased the number of rearing bouts in an open field, possibly suggesting an increase in attentiveness. These data indicate that ketamine can buffer a fear response when given a week before as prophylactic, but not when given immediately before or after a stress-inducing episode. Thus, ketamine may be most useful in the clinic if administered in a prophylactic fashion 1 week before a stressor in order to protect against heightened fear responses to aversive stimuli.

McGowan, J. C., LaGamma, C. T., Lim, S. C., Tsitsiklis, M., Neria, Y., Brachman, R. A., & Denny, C. A. (2017). Prophylactic Ketamine Attenuates Learned Fear. Neuropsychopharmacology. 10.1038/npp.2017.19
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Psychedelics in Palliative Care: Clinical and Ethical Considerations - October 27th

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