Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling. DOI Open Access
Jonah A. Padawer-Curry, Oliver J. Krentzman, Chao‐Cheng Kuo

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 24, 2023

Psychedelics hold therapeutic promise for mood disorders due to rapid, sustained results. Human neuroimaging studies have reported dramatic serotonin-2A receptor-(5-HT2AR)-dependent changes in functional brain reorganization that presumably reflect neuromodulation. However, the potent vasoactive effects of serotonin been overlooked. We found psilocybin-mediated alterations fMRI-HRFs humans, suggesting potentially altered NVC. To assess neuronal, hemodynamic, and neurovascular coupling (NVC) psychedelic 5-HT2AR agonist, 2,5-Dimethoxy-4-iodoamphetamine (DOI), wide-field optical imaging (WFOI) was used awake Thy1-jRGECO1a mice during stimulus-evoked resting-state conditions. While DOI partially tasked-based NVC, more pronounced NVC occurred under conditions were strongest association regions. Further, calcium hemodynamic activity different accounts RSFC DOI. Co-administration antagonist, MDL100907, reversed many these effects. Dissociation between neuronal signals emphasizes a need consider psychedelics when interpreting blood-oxygenation-dependent measures.

Language: Английский

Psychedelics as Transformative Therapeutics DOI
Bryan L. Roth, Ryan H. Gumpper

American Journal of Psychiatry, Journal Year: 2023, Volume and Issue: 180(5), P. 340 - 347

Published: May 1, 2023

Over the past decade, psychedelic compounds have emerged as potentially transformative therapeutics for a variety of intractable neuropsychiatric conditions. However, historically most basic science has utilized these probes to interrogate various endogenous neurotransmitter systems-mainly serotonin 5-HT2A receptor. With renewed interest in utilizing and explosion clinical trials, psychedelics been purported treat many disorders, including depression, cluster headaches, migraines, anxiety, obsessive-compulsive disorder. It is therefore imperative understand biology pharmacology behind their therapeutic mechanisms well expose any potential pitfalls widespread use treatments. This review covers latest advances understanding biological mechanisms, newest efforts drug discovery, when it comes this class emerging therapeutics.

Language: Английский

Citations

39
Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles DOI Creative Commons

Sophie A. Rogers,

Elizabeth A. Heller, Gregory Corder

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 4, 2024

Abstract The serotonin 2 receptor (5HT2R) agonist psilocybin displays rapid and persistent therapeutic efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. However, the impact of on patterns neural activity underlying sustained changes in behavioral flexibility has not been characterized. To test hypothesis that enhances altering cortical ensembles, we performed longitudinal single-cell calcium imaging retrosplenial cortex a five-day trace fear learning extinction assay. A single dose induced ensemble turnover between days while oppositely modulating fearand extinctionactive neurons. acute suppression fear-active neurons delayed recruitment extinction-active were predictive psilocybin-enhanced extinction. computational model revealed inhibition is sufficient to explain its effects later. These results align with our introduce new mechanism involving populations cortex.

Language: Английский

Citations

7
Psychedelics: preclinical insights provide directions for future research DOI
Ryan H. Gumpper, Bryan L. Roth

Neuropsychopharmacology, Journal Year: 2023, Volume and Issue: 49(1), P. 119 - 127

Published: March 17, 2023

Language: Английский

Citations

15
Neural circuit-selective, multiplexed pharmacological targeting of prefrontal cortex-projecting locus coeruleus neurons drives antinociception DOI Creative Commons
Chao‐Cheng Kuo, Jordan G. McCall

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 8, 2024

Selective manipulation of neural circuits using optogenetics and chemogenetics holds great translational potential but requires genetic access to neurons. Here, we demonstrate a general framework for identifying tool-independent, pharmacological strategies circuit-selective modulation. We developed an economically accessible calcium imaging-based approach large-scale scans endogenous receptor-mediated activity. As testbed this approach, used the mouse locus coeruleus due combination its widespread, modular efferent circuitry wide variety endogenously expressed GPCRs. Using machine learning-based action deconvolution retrograde tracing, identified agonist cocktail that selectively inhibits medial prefrontal cortex-projecting

Language: Английский

Citations

4
The Selective 5HT2A Receptor Agonist, 25CN‐NBOH Exerts Excitatory and Inhibitory Cellular Actions on Mouse Medial Prefrontal Cortical Neurons DOI Creative Commons
Yang Wang, Jesper L. Kristensen, Kristi A. Kohlmeier

et al.

Synapse, Journal Year: 2025, Volume and Issue: 79(2)

Published: March 1, 2025

Abstract Psychedelic compounds have gained renewed interest due to their rapid and long‐lasting therapeutic effects on stress‐related disorders. While the underlying mechanisms of actions psychedelic are still unclear, these drugs thought modulate activity serotonergic system, primarily through activating serotonin type 2A receptor (5‐HT R) studies focused in medial prefrontal cortex (mPFC). 25CN‐NBOH, a synthetic compound with high binding affinity for 5‐HT Rs anti‐anxiety actions, has emerged as valuable tool investigating physiological functions mediated by this receptor. This study aimed investigate electrophysiological 25CN‐NBOH pyramidal mPFC neurons using whole‐cell patch clamp recordings mouse brain slices. We recorded synaptic events action potential rates during acute long‐term exposure two concentrations 25CN‐NBOH. Acute application 10 µM increased frequency spontaneous excitatory postsynaptic currents (sEPSCs) that was reliant activation R, which not seen upon chronic exposure. A similar effect 200 nM noted. Surprisingly, both significantly suppressed firing rate following well longer‐term 1 h. suppression independent R but M‐current channels, evidenced reversal blocker XE‐991. Our data suggest complicated dual enhancing transmission while also reducing excitability. contribute knowledge regarding cellular consequence agonism widening our understanding psychedelics.

Language: Английский

Citations

0
Cellular rules underlying psychedelic control of prefrontal pyramidal neurons DOI Creative Commons
Tyler G. Ekins, Isla Brooks, Sameer Kailasa

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 23, 2023

Classical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation serotonin 2

Language: Английский

Citations

9
A suite of engineered mice for interrogating psychedelic drug actions DOI Creative Commons

Yi-Ting Chiu,

Ariel Y. Deutch,

Wei Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 26, 2023

Psychedelic drugs like lysergic acid diethylamide (LSD) and psilocybin have emerged as potentially transformative therapeutics for many neuropsychiatric diseases, including depression, anxiety, post-traumatic stress disorder, migraine, cluster headaches. LSD exert their psychedelic effects via activation of the 5-hydroxytryptamine 2A receptor (HTR2A). Here we provide a suite engineered mice useful clarifying role HTR2A HTR2A-expressing neurons in drug actions. We first generated

Language: Английский

Citations

8
The Effects of Psychedelics on Neuronal Physiology DOI
Cassandra J. Hatzipantelis, David E. Olson

Annual Review of Physiology, Journal Year: 2023, Volume and Issue: 86(1), P. 27 - 47

Published: Nov. 6, 2023

Psychedelics are quite unique among drugs that impact the central nervous system, as a single administration of psychedelic can both rapidly alter subjective experience in profound ways and produce sustained effects on circuits relevant to mood, fear, reward, cognitive flexibility. These remarkable properties direct result psychedelics interacting with several key neuroreceptors distributed across brain. Stimulation these receptors activates variety signaling cascades ultimately culminate changes neuronal structure function. Here, we describe physiology, highlighting their acute serotonergic glutamatergic neurotransmission well long-lasting structural functional neuroplasticity cortex. We propose neurobiological leading might be distinct, which could provide opportunities for engineering compounds optimized safety efficacy profiles.

Language: Английский

Citations

6
Psychedelic 5-HT2A receptor agonism: neuronal signatures and altered neurovascular coupling. DOI Open Access
Jonah A. Padawer-Curry, Oliver J. Krentzman, Chao‐Cheng Kuo

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 24, 2023

Psychedelics hold therapeutic promise for mood disorders due to rapid, sustained results. Human neuroimaging studies have reported dramatic serotonin-2A receptor-(5-HT2AR)-dependent changes in functional brain reorganization that presumably reflect neuromodulation. However, the potent vasoactive effects of serotonin been overlooked. We found psilocybin-mediated alterations fMRI-HRFs humans, suggesting potentially altered NVC. To assess neuronal, hemodynamic, and neurovascular coupling (NVC) psychedelic 5-HT2AR agonist, 2,5-Dimethoxy-4-iodoamphetamine (DOI), wide-field optical imaging (WFOI) was used awake Thy1-jRGECO1a mice during stimulus-evoked resting-state conditions. While DOI partially tasked-based NVC, more pronounced NVC occurred under conditions were strongest association regions. Further, calcium hemodynamic activity different accounts RSFC DOI. Co-administration antagonist, MDL100907, reversed many these effects. Dissociation between neuronal signals emphasizes a need consider psychedelics when interpreting blood-oxygenation-dependent measures.

Language: Английский

Citations

5