Single-dose psychedelic enhances cognitive flexibility and reversal learning in mice weeks after administration DOI

Elizabeth J. Brouns,

Tyler G. Ekins, Omar J. Ahmed

et al.

Psychedelics., Journal Year: 2025, Volume and Issue: unknown, P. 1 - 7

Published: April 22, 2025

Psychedelic compounds have demonstrated remarkable therapeutic potential for treating neuropsychiatric disorders by promoting sustained neuroplasticity in the prefrontal cortex (PFC). Cognitive flexibility—the ability to adapt previously learned rules novel situations—represents a critical PFC function that is frequently impaired depression, PTSD, and neurodegenerative conditions. In this study, we demonstrate single administration of selective serotonin 2A receptor agonist 25CN-NBOH produces significant, long-lasting improvements cognitive flexibility both male female mice when measured 2–3 weeks posttreatment. Using automated sequential learning paradigm, psychedelic-treated showed superior adaptability rule reversal tasks compared saline controls, as evidenced enhanced poke efficiency, higher percentages correct trials, increased reward acquisition. These behavioral findings complement existing cellular research showing psychedelic-induced structural remodeling uniquely benefits persisting after psychedelic dose. Our task provides high-throughput method evaluating effects various compounds, offering important implications applications conditions characterized rigidity, including potentially Alzheimer's disease.

Language: Английский

Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential DOI Creative Commons
Jason Wallach,

Andrew B. Cao,

Maggie M. Calkins

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 15, 2023

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 recruitment efficacy predicts potential, assessed using head-twitch response (HTR) magnitude in male mice. further disrupting Gq-PLC signaling attenuates the HTR threshold level is required to induce psychedelic-like consistent fact certain partial agonists (e.g., lisuride) are non-psychedelic. Understanding role Gq-efficacy psychopharmacology permits rational development non-psychedelic agonists. also demonstrate block effects downregulation tachyphylaxis. Overall, Gq-signaling can be fine-tuned generate distinct from classical psychedelics.

Language: Английский

Citations

45
TrkB transmembrane domain: bridging structural understanding with therapeutic strategy DOI Creative Commons
Giray Enkavi, Mykhailo Girych, Rafael Moliner

et al.

Trends in Biochemical Sciences, Journal Year: 2024, Volume and Issue: 49(5), P. 445 - 456

Published: March 2, 2024

TrkB (neuronal receptor tyrosine kinase-2, NTRK2) is the for brain-derived neurotrophic factor (BDNF) and a critical regulator of activity-dependent neuronal plasticity. The past few years have witnessed an increasing understanding structure function TrkB, including its transmembrane domain (TMD). interacts with membrane cholesterol, which bidirectionally regulates signaling. Additionally, has recently been recognized as binding target antidepressant drugs. A variety different antidepressants, typical rapid-acting well psychedelic compounds, act allosteric potentiators BDNF signaling through TrkB. This suggests that common compounds. Although more research needed, current knowledge promising further drug development.

Language: Английский

Citations

18
Pharmacological characterization of cannabidiol as a negative allosteric modulator of the 5-HT2A receptor DOI

Étienne Billard,

Alexandre Torbey,

Antonio Inserra

et al.

Cellular Signalling, Journal Year: 2025, Volume and Issue: 127, P. 111588 - 111588

Published: Jan. 5, 2025

Language: Английский

Citations

4
Psychedelics for the Treatment of Psychiatric Disorders: Interpreting and Translating Available Evidence and Guidance for Future Research DOI

Roger S. McIntyre,

Angela T.H. Kwan, Rodrigo B. Mansur

et al.

American Journal of Psychiatry, Journal Year: 2025, Volume and Issue: 182(1), P. 21 - 32

Published: Jan. 1, 2025

During the past decade, there has been extraordinary public, media, and medical research interest in psychedelics as promising therapeutics for difficult-to-treat psychiatric disorders. Short-term controlled trial data suggest that certain are effective safe treatment of major depressive disorder, treatment-resistant depression, posttraumatic stress disorder. Preliminary evidence also supports efficacy other disorders (e.g., tobacco alcohol use disorders). Notwithstanding promise psychedelics, concerns have arisen with respect to interpretability translatability study results. For example, aspects related short- long-term safety, abuse liability, essentiality psychedelic "trip" psychological support are, inter alia, insufficiently characterized agents. The overarching aims this overview 1) review methodological affect inferences interpretation extant studies disorders, 2) provide guidance future development psychiatry, critical clinical implementation.

Language: Английский

Citations

2
Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments DOI Creative Commons
John H. Krystal, Alfred P. Kaye, Sarah Jefferson

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(49)

Published: Nov. 27, 2023

Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy treatment-resistant symptoms, protection against relapse distinguish it from prior antidepressants. discovery reconceptualization the neurobiology depression and, in turn, insights elaboration its mechanisms action inform studies pathophysiology related disorders. It been 25 y since we first presented our ketamine findings Thus, is timely this review to consider what have learned suggest future directions optimization rapid-acting antidepressant treatment.

Language: Английский

Citations

35
Therapeutic mechanisms of psychedelics and entactogens DOI
Boris D. Heifets, David E. Olson

Neuropsychopharmacology, Journal Year: 2023, Volume and Issue: 49(1), P. 104 - 118

Published: July 24, 2023

Language: Английский

Citations

30
Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants DOI
Wenwen Duan, Dongmei Cao, Sheng Wang

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 124(1), P. 124 - 163

Published: Nov. 30, 2023

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). Clinical trials have demonstrated traditional psychedelic substances like psilocybin as class rapid-acting and long-lasting antidepressants. However, there is pressing need for rationally designed 5-HT2AR agonists possess optimal pharmacological profiles in order to fully reveal therapeutic potential these identify safer drug candidates devoid effects. This Perspective provides an overview structure–activity relationships existing based on their chemical classifications discusses recent advancements understanding molecular pharmacology at structural level. The encouraging clinical outcomes psychedelics depression treatment sparked discovery endeavors aimed developing novel with improved subtype selectivity signaling bias properties, which could serve potentially nonhallucinogenic These efforts can be significantly expedited through utilization structure-based methods functional selectivity-directed screening.

Language: Английский

Citations

30
1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents – A Review DOI Creative Commons
Richard A. Glennon, Małgorzata Dukat

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(6), P. 1722 - 1745

Published: May 8, 2024

1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI, or DOX where X = −I) was first synthesized in 1973 a structure–activity study to explore the effect of various aryl substituents on then newly identified, and subsequently controlled, hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, −CH3). Over time, DOI found be serotonin (5-HT) receptor agonist using peripheral 5-HT tissue assays later, following identification multiple families central receptors, an at 5-HT2 receptors rat and, then, human brain. Today, classical hallucinogens, currently referred as serotonergic psychedelic agents, are receiving considerable attention for their potential therapeutic application neuropsychiatric disorders including treatment-resistant depression. Here, we review, historical current developments that led becoming unique, perhaps landmark, research.

Language: Английский

Citations

10
G protein-specific mechanisms in the serotonin 5-HT2A receptor regulate psychosis-related effects and memory deficits DOI Creative Commons
Elk Kossatz, Rebeca Dı́ez-Alarcia,

Supriya A. Gaitonde

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: May 29, 2024

Abstract G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular pathways upon activation. Complete (in)activation of all can be counterproductive for specific therapeutic applications. This is the case serotonin 2 A receptor (5-HT 2A R), a prominent target treatment schizophrenia. In this study, we elucidate complex 5-HT R coupling signature in response different probes, and its physiological consequences by combining computational modeling, vitro vivo experiments with human postmortem brain studies. We show how chemical modification endogenous agonist dramatically impacts protein profile associated behavioral responses. Importantly, among these responses, demonstrate that memory deficits regulated αq activation, whereas psychosis-related behavior modulated through αi1 stimulation. These findings emphasize complexity GPCR pharmacology physiology open path designing improved therapeutics stchizophrenia.

Language: Английский

Citations

10
Psilocybin: From Psychiatric Pariah to Perceived Panacea DOI
Gregory A. Fonzo, Aaron Wolfgang,

Bryan Barksdale

et al.

American Journal of Psychiatry, Journal Year: 2025, Volume and Issue: 182(1), P. 54 - 78

Published: Jan. 1, 2025

The authors critically examine the evidence base for psilocybin administered with psychological support/therapy (PST) in treatment of psychiatric disorders and offer practical recommendations to guide future research endeavors.

Language: Английский

Citations

1