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Effect of a Hallucinogenic Serotonin 5-HT2A Receptor Agonist on Visually-Guided, Hippocampal-Dependent Spatial Cognition in C57BL/6J Mice

February 1, 2017 / Neuroscience, Papers, Psychology, Publications / By / , ,

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

February 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / ,

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

February 1, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , ,

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

January 31, 2017 / Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / By /

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

January 29, 2017 / Anxiety Disorders / PTSD, Ketamine, Papers, Psychology / By / , ,

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

January 29, 2017 / Anxiety Disorders / PTSD, Ketamine, Papers, Psychology / By / , ,

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

January 27, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

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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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

January 27, 2017 / Ayahuasca, Depressive Disorders, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery-Asberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0.019; Cohen’s d=0.98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0.04; at D7, p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d=0.84; D2: Cohen’s d=0.84; D7: Cohen’s d=1.49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4.95; p = 0.04; NNT = 2.66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M., Pessoa, J., … & Tofoli, L. (2017). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial. bioRxiv, 103531. 10.1101/103531
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The Fabric of Meaning and Subjective Effects in LSD-Induced States Depend on Serotonin 2A Receptor Activation

January 26, 2017 / LSD, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , , ,

Abstract

A core aspect of the human self is the attribution of personal relevance to everyday stimuli enabling us to experience our environment as meaningful [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][1]. However, abnormalities in the attribution of personal relevance to sensory experiences are also critical features of many psychiatric disorders [2 and 3]. Despite their clinical relevance, the neurochemical and anatomical substrates enabling meaningful experiences are largely unknown. Therefore, we investigated the neuropharmacology of personal relevance processing in humans by combining fMRI and the administration of the mixed serotonin (5-HT) and dopamine receptor (R) agonist lysergic acid diethylamide (LSD), well known to alter the subjective meaning of percepts, with and without pretreatment with the 5-HT2AR antagonist ketanserin. General subjective LSD effects were fully blocked by ketanserin. In addition, ketanserin inhibited the LSD-induced attribution of personal relevance to previously meaningless stimuli and modulated the processing of meaningful stimuli in cortical midline structures. These findings point to the crucial role of the 5-HT2AR subtype and cortical midline regions in the generation and attribution of personal relevance. Our results thus increase our mechanistic understanding of personal relevance processing and reveal potential targets for the treatment of psychiatric illnesses characterized by alterations in personal relevance attribution.

Preller, K. H., Herdener, M., Pokorny, T., Planzer, A., Kraehenmann, R., Stämpfli, P., … & Vollenweider, F. X. (2017). The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Current Biology, 27(3), 451-457. 10.1016/j.cub.2016.12.030
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A Receptor on Acid

January 26, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

Wacker et al. report the crystal structure of LSD in complex with one of its major targets in the brain, the 5-HT2B receptor, the first such structure for any psychedelic drug. The results shed light on the molecular mechanisms underlying its ability to induce hallucinations with greater duration and potency than closely related compounds.
Chen, Q., & Tesmer, J. J. (2017). A receptor on acid. Cell, 168(3), 339-341. 10.1016/j.cell.2017.01.012
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