Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors

Science, Год журнала: 2023, Номер 379(6633), С. 700 - 706

Опубликована: Фев. 16, 2023

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and ability to promote cortical neuron growth has been hypothesized underlie rapid sustained therapeutic effects psychedelics. Activation 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) essential for psychedelic-induced plasticity, but it currently unclear why some 5-HT2AR agonists neuroplasticity, whereas others do not. We used molecular genetic tools demonstrate that intracellular 5-HT2ARs mediate plasticity-promoting properties psychedelics; these results explain serotonin does not engage similar plasticity mechanisms. This work emphasizes role location bias signaling, identifies as target, raises intriguing possibility might be endogenous ligand cortex.

Язык: Английский

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Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Nature Neuroscience, Год журнала: 2023, Номер 26(6), С. 1032 - 1041

Опубликована: Июнь 1, 2023

Abstract Psychedelics produce fast and persistent antidepressant effects induce neuroplasticity resembling the of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine ketamine, act by binding to TrkB, receptor for BDNF. Here we show lysergic acid diethylamide (LSD) psilocin directly bind TrkB with affinities 1,000-fold higher than those other psychedelics antidepressants distinct but partially overlapping sites within transmembrane domain dimers. The on neurotrophic signaling, plasticity antidepressant-like behavior in mice depend promotion endogenous BDNF signaling are independent serotonin 2A (5-HT ) activation, whereas LSD-induced head twitching is dependent 5-HT binding. Our data confirm as a common primary target suggest high-affinity positive allosteric modulators lacking activity may retain potential without hallucinogenic effects.

Язык: Английский

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The neural basis of psychedelic action

Nature Neuroscience, Год журнала: 2022, Номер 25(11), С. 1407 - 1419

Опубликована: Окт. 24, 2022

Язык: Английский

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Psychedelic therapy for depressive symptoms: A systematic review and meta-analysis

Journal of Affective Disorders, Год журнала: 2022, Номер 322, С. 194 - 204

Опубликована: Окт. 7, 2022

Язык: Английский

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Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity

Biochemistry, Год журнала: 2022, Номер 61(3), С. 127 - 136

Опубликована: Янв. 21, 2022

In addition to producing profound subjective effects following acute administration, psychedelic compounds can induce beneficial behavioral changes relevant the treatment of neuropsychiatric disorders that last long after have been cleared from body. One hypothesis with potential explain remarkable enduring psychedelics is related their abilities promote structural and functional neuroplasticity in prefrontal cortex (PFC). A hallmark many stress-related diseases, including depression, post-traumatic stress disorder (PTSD), addiction, atrophy neurons PFC. Psychedelics appear be particularly effective catalysts for growth these key neurons, ultimately leading restoration synaptic connectivity this critical brain region. Furthermore, evidence suggests hallucinogenic are not directly linked ability neuroplasticity. If we develop improved alternatives treating must fully characterize molecular mechanisms give rise psychedelic-induced Here, I review our current understanding biochemical signaling pathways activated by neuroplasticity-promoting molecules, an emphasis on unanswered questions.

Язык: Английский

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Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin

ACS Chemical Neuroscience, Год журнала: 2023, Номер 14(3), С. 468 - 480

Опубликована: Янв. 11, 2023

Psilocybin is a psychedelic with therapeutic potential. While there growing evidence that psilocybin exerts its beneficial effects through enhancing neural plasticity, the exact brain regions involved are not completely understood. Determining impact of on plasticity-related gene expression throughout can broaden our understanding circuits in psychedelic-evoked plasticity. In this study, whole-brain serial two-photon microscopy and light sheet were employed to map immediate early gene, c-Fos, male female mice. The drug-induced c-Fos following administration was compared subanesthetic ketamine saline control. produced acutely comparable elevations numerous regions, including anterior cingulate cortex, locus coeruleus, primary visual central basolateral amygdala, medial lateral habenula, claustrum. Select exhibited drug-preferential differences, such as dorsal raphe insular cortex for CA1 subfield hippocampus ketamine. To gain insights into contributions receptors cell types, maps related brain-wide situ hybridization data. transcript analyses showed endogenous levels

Язык: Английский

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New and emerging approaches to treat psychiatric disorders

Nature Medicine, Год журнала: 2023, Номер 29(2), С. 317 - 333

Опубликована: Фев. 1, 2023

Язык: Английский

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5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines

ACS Chemical Neuroscience, Год журнала: 2023, Номер 14(3), С. 351 - 358

Опубликована: Янв. 11, 2023

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns limit clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding how these molecules produce therapeutic effects. While the hallucinogenic properties are generally attributed to activation serotonin 2A receptors (5-HT2ARs), it is currently unclear if also mediate as several nonhallucinogenic analogues with antidepressant-like been developed. Moreover, many exhibit promiscuous pharmacology, making challenging identify primary target(s). Here, we use combination pharmacological genetic tools demonstrate 5-HT2A essential for tryptamine-based Our results suggest psychedelic tryptamines through same receptor.

Язык: Английский

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Psilocybin-assisted therapy for depression: A systematic review and meta-analysis

Psychiatry Research, Год журнала: 2023, Номер 329, С. 115531 - 115531

Опубликована: Окт. 11, 2023

Язык: Английский

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The Potential of Flavonoids and Flavonoid Metabolites in the Treatment of Neurodegenerative Pathology in Disorders of Cognitive Decline

Antioxidants, Год журнала: 2023, Номер 12(3), С. 663 - 663

Опубликована: Март 7, 2023

Flavonoids are a biodiverse family of dietary compounds that have antioxidant, anti-inflammatory, antiviral, and antibacterial cell protective profiles. They received considerable attention as potential therapeutic agents in biomedicine been widely used traditional complimentary medicine for generations. Such medical herbal formulations extremely complex mixtures many pharmacologically active provide outcome through network pharmacological effects complexity. Methods emerging to determine the components their targets decipher complexities how pharmacology provides such effects. The gut microbiome has important roles play generation bioactive flavonoid metabolites retaining or exceeding antioxidative anti-inflammatory properties intact and, some cases, new antitumor antineurodegenerative bioactivities. Certain food items identified with high prebiotic profiles suggesting neutraceutical supplementation may be beneficially employed preserve healthy population bacterial symbiont species minimize establishment harmful pathogenic organisms. Gut health is an consideration effecting overall wellbeing linked organ systems. Bioconversion generates can also transported by vagus nerve systemic circulation brain populations exert beneficial effect. This particularly number neurological disorders (autism, bipolar disorder, AD, PD) characterized on moods, resulting depression anxiety, impaired motor function, long-term cognitive decline. Native flavonoids alleviation inflammation tissues, however, concerns raised levels not achieved, thus allowing them display optimal Dietary manipulation vagal stimulation both yielded responses treatment autism spectrum disorders, depression, establishing route communication gut-brain axis established disease intervention. While native known penetrate blood–brain barrier, microbiome-generated (e.g., protocatechuic acid, urolithins, γ-valerolactones), which retain antioxidant potency addition promote mitochondrial cerebrovascular microcapillary should considered biotherapeutic agents. Studies warranted experimentally examine efficacy directly, they emerge novel options.

Язык: Английский

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