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Neuroscience

Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system

November 17, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the ‘oxidative phosphorylation’ (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response.
Weckmann, K., Deery, M. J., Howard, J. A., Feret, R., Asara, J. M., Dethloff, F., … & Webhofer, C. (2017). Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system. Scientific reports, 7(1), 15788. 10.1038/s41598-017-16183-x
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Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system

November 17, 2017 / Depressive Disorders, Ketamine, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the ‘oxidative phosphorylation’ (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response.
Weckmann, K., Deery, M. J., Howard, J. A., Feret, R., Asara, J. M., Dethloff, F., … & Webhofer, C. (2017). Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system. Scientific reports, 7(1), 15788. 10.1038/s41598-017-16183-x
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LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm

October 31, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Under the predictive coding framework, perceptual learning and inference are dependent on the interaction between top-down predictions and bottom-up sensory signals both between and within regions in a network. However, how such feedback and feedforward connections are modulated in the state induced by lysergic acid diethylamide (LSD) is poorly understood. In this study, an auditory oddball paradigm was presented to healthy participants (16 males, 4 female) under LSD and placebo, and brain activity was recorded using magnetoencephalography (MEG). Scalp level Event Related Fields (ERF) revealed reduced neural adaptation to familiar stimuli, and a blunted neural ‘surprise’ response to novel stimuli in the LSD condition. Dynamic causal modelling revealed that both the presentation of novel stimuli and LSD modulate backward extrinsic connectivity within a task-activated fronto-temporal network, as well as intrinsic connectivity in the primary auditory cortex. These findings show consistencies with those of previous studies of schizophrenia and ketamine but also studies of reduced consciousness – suggesting that rather than being a marker of conscious level per se, backward connectivity may index modulations of perceptual learning common to a variety of altered states of consciousness, perhaps united by a shared altered sensitivity to environmental stimuli. Since recent evidence suggests that the psychedelic state may correspond to a heightened ‘level’ of consciousness with respect to the normal waking state, our data warrant a re-examination of the top-down hypotheses of conscious level and suggest that several altered states may feature this specific biophysical effector.
Timmermann, C., Spriggs, M. J., Kaelen, M., Leech, R., Nutt, D. J., Moran, R. J., … & Muthukumaraswamy, S. D. (2017). LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm. Neuropharmacology. 10.1016/j.neuropharm.2017.10.039
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Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

October 13, 2017 / Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., … & Leech, R. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific reports, 7(1), 13187. 10.1038/s41598-017-13282-7
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Salvinorin A reduces neuropathic nociception in the insular cortex of the rat

October 4, 2017 / Neuroscience, Papers, Psychiatry & Medicine, Publications, Salvia / Salvinorin A / By / , , , , , ,

Abstract

BACKGROUND:
Neuropathic pain is one of the most important challenges in public health. The search for novel treatments is important for an adequate relief without adverse effects. In this sense salvinorin A (SA), the main diterpene of the medicinal plant Salvia divinorum is an important antinociceptive compound, which acts as a potent agonist of kappa opioid receptor (KOR) and cannabinoid CB1 receptors.
METHODS:
We evaluated nociceptive responses in a neuropathic pain model induced by the sciatic nerve ligature (SNL) in the right hind paw, after the microinjection of SA, Salvinorin B (SB), KOR and CB1 antagonists directly in the insular cortex (IC) in male wistar rats.
RESULTS:
We found a potent antinociceptive effect with the administration of SA. Moreover, this effect was blocked by the administration of a KOR antagonist as well as the administration of a CB1 antagonist.
CONCLUSION:
Salvinorin A has a potent antinociceptive effect when is administered centrally in the IC by the interaction with KOR and CB1 receptors.
SIGNIFICANCE:
We show evidence on the effectiveness of the administration of salvinorin A in the IC in a rodent model of neuropathic pain. These results support the use of novel compounds like SA as a therapeutic alternative for neuropathic pain relief.
Coffeen, U., Canseco‐Alba, A., Simón‐Arceo, K., Almanza, A., Mercado, F., León‐Olea, M., & Pellicer, F. (2017). Salvinorin A reduces neuropathic nociception in the insular cortex of the rat. European Journal of Pain. 10.1002/ejp.1120
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Acute LSD effects on response inhibition neural networks

October 2, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

BACKGROUND:
Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations.
METHODS:
In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire.
RESULTS:
Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery.
CONCLUSION:
Our findings show that 5-HT2AR activation by LSD leads to a hippocampal-prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.
Schmidt, A., Müller, F., Lenz, C., Dolder, P. C., Schmid, Y., Zanchi, D., … & Borgwardt, S. (2017). Acute LSD effects on response inhibition neural networks. Psychological Medicine, 1-13. 10.1017/S0033291717002914
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N,N-dimethyltryptamine and the pineal gland: Separating fact from myth

October 1, 2017 / DMT, Neuroscience, Papers, Psychology, Publications / By /

Abstract

The pineal gland has a romantic history, from pharaonic Egypt, where it was equated with the eye of Horus, through various religious traditions, where it was considered the seat of the soul, the third eye, etc. Recent incarnations of these notions have suggested that N,N-dimethyltryptamine is secreted by the pineal gland at birth, during dreaming, and at near death to produce out of body experiences. Scientific evidence, however, is not consistent with these ideas. The adult pineal gland weighs less than 0.2 g, and its principal function is to produce about 30 µg per day of melatonin, a hormone that regulates circadian rhythm through very high affinity interactions with melatonin receptors. It is clear that very minute concentrations of N,N-dimethyltryptamine have been detected in the brain, but they are not sufficient to produce psychoactive effects. Alternative explanations are presented to explain how stress and near death can produce altered states of consciousness without invoking the intermediacy of N,N-dimethyltryptamine.
Nichols, D. E. (2017). N, N-dimethyltryptamine and the pineal gland: Separating fact from myth. Journal of Psychopharmacology, 0269881117736919.
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The Mechanisms of Psychedelic Visionary Experiences: Hypotheses from Evolutionary Psychology

September 10, 2024 / Neuroscience, Papers, Psychology, Publications, Scienitific Discipline / By /

Abstract

Neuropharmacological effects of psychedelics have profound cognitive, emotional, and social effects that inspired the development of cultures and religions worldwide. Findings that psychedelics objectively and reliably produce mystical experiences press the question of the neuropharmacological mechanisms by which these highly significant experiences are produced by exogenous neurotransmitter analogs. Humans have a long evolutionary relationship with psychedelics, a consequence of psychedelics’ selective effects for human cognitive abilities, exemplified in the information rich visionary experiences. Objective evidence that psychedelics produce classic mystical experiences, coupled with the finding that hallucinatory experiences can be induced by many non-drug mechanisms, illustrates the need for a common model of visionary effects. Several models implicate disturbances of normal regulatory processes in the brain as the underlying mechanisms responsible for the similarities of visionary experiences produced by psychedelic and other methods for altering consciousness. Similarities in psychedelic-induced visionary experiences and those produced by practices such as meditation and hypnosis and pathological conditions such as epilepsy indicate the need for a general model explaining visionary experiences. Common mechanisms underlying diverse alterations of consciousness involve the disruption of normal functions of the prefrontal cortex and default mode network (DMN). This interruption of ordinary control mechanisms allows for the release of thalamic and other lower brain discharges that stimulate a visual information representation system and release the effects of innate cognitive functions and operators. Converging forms of evidence support the hypothesis that the source of psychedelic experiences involves the emergence of these innate cognitive processes of lower brain systems, with visionary experiences resulting from the activation of innate processes based in the mirror neuron system (MNS).
Winkelman, M. J. (2017). The Mechanisms of Psychedelic Visionary Experiences: Hypotheses from Evolutionary Psychology. Frontiers in Neuroscience, 11, 539. 10.3389/fnins.2017.00539
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Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music

September 28, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.
Barrett, F. S., Preller, K. H., Herdener, M., Janata, P., & Vollenweider, F. X. (2017). Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music. Cerebral Cortex, 1-12. 10.1093/cercor/bhx257
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Psychedelic Drugs in Biomedicine

September 22, 2017 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Substance Use Disorder / By / , , , ,

Abstract

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients.
Kyzar, E. J., Nichols, C. D., Gainetdinov, R. R., Nichols, D. E., & Kalueff, A. V. (2017). Psychedelic Drugs in Biomedicine. Trends in Pharmacological Sciences. 10.1016/j.tips.2017.08.003
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