Preclinical perspectives on the mechanisms underlying the therapeutic actions of psilocybin in psychiatric disorders

Wulff, Andreas B.; Nichols, Charles D.; Thompson, Scott M.

doi:10.1016/j.neuropharm.2023.109504

Cited by 11 publications

(4 citation statements)

References 117 publications

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“…Three main structural classes of serotonergic hallucinogens include ergolines (e.g., LSD), tryptamines (e.g., psilocybin, converted by the body to the active molecule psilocin) and phenethylamines [e.g., 2,5-dimethoxy-4-methylamphetamine ( DOM ), 2,5-dimethoxy-4-iodophenyl]-2-aminopropane ( DOI )]. These compounds share close structural similarity to the endogenous tryptamine 5-HT ( Gaddum and Hameed, 1954 ) which spurred the discovery that 5-HT 2A R agonist efficacy is a key mechanism of action for this class of compounds to evoke overlapping and powerful subjective effects in humans ( Nichols and Walter, 2021 ), although psychedelic pharmacology is complex and nuanced ( Howell and Cunningham, 2015 ; Castellanos et al, 2020 ; McClure-Begley and Roth, 2022 ; Wulff et al, 2023 ). While the presumed abuse liability and limited medical value historically restricted clinical studies of psychedelics ( Henningfield et al, 2022 ; Hendricks et al, 2023 ), 5-HT 2A R neurotransmission was established to mediate hallucinations in schizophrenia and Parkinson’s disease psychosis ( Schmidt et al, 1995 ; Ballanger et al, 2010 ; Hacksell et al, 2014 ; Cho et al, 2017 ).…”

Section: Psychedelic Pharmacologymentioning

confidence: 99%

“…The case for the role of the 5-HT 2A R in the mechanisms of action of psychedelics is strong, but we would be remiss to overlook the fact that distinct in vitro and in vivo profiles are recognized across psychedelic molecules which variably bind to multiple 5-HT receptors, dopamine D 1 receptor ( D 1 R ) and D 2 R, as well as other brain-localized targets ( Howell and Cunningham, 2015 ; Castellanos et al, 2020 ; McClure-Begley and Roth, 2022 ; Wulff et al, 2023 ). For instance, LSD potently binds to human 5-HT 2A R but also 5-HT 1A R, 5-HT 2C R, D 2 R and with some affinity for α adrenergic, D 1 R and D 3 R ( Rickli et al, 2015 ; Rickli et al, 2016 ).…”

Section: Psychedelic Pharmacologymentioning

confidence: 99%

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μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

Salinsky,

Merritt,

Zamora

et al. 2023

Front. Pharmacol.

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Opioid misuse and opioid-involved overdose deaths are a massive public health problem involving the intertwined misuse of prescription opioids for pain management with the emergence of extremely potent fentanyl derivatives, sold as standalone products or adulterants in counterfeit prescription opioids or heroin. The incidence of repeated opioid overdose events indicates a problematic use pattern consistent with the development of the medical condition of opioid use disorder (OUD). Prescription and illicit opioids reduce pain perception by activating µ-opioid receptors (MOR) localized to the central nervous system (CNS). Dysregulation of meso-corticolimbic circuitry that subserves reward and adaptive behaviors is fundamentally involved in the progressive behavioral changes that promote and are consequent to OUD. Although opioid-induced analgesia and the rewarding effects of abused opioids are primarily mediated through MOR activation, serotonin (5-HT) is an important contributor to the pharmacology of opioid abused drugs (including heroin and prescription opioids) and OUD. There is a recent resurgence of interest into psychedelic compounds that act primarily through the 5-HT2A receptor (5-HT2AR) as a new frontier in combatting such diseases (e.g., depression, anxiety, and substance use disorders). Emerging data suggest that the MOR and 5-HT2AR crosstalk at the cellular level and within key nodes of OUD circuitry, highlighting a major opportunity for novel pharmacological intervention for OUD. There is an important gap in the preclinical profiling of psychedelic 5-HT2AR agonists in OUD models. Further, as these molecules carry risks, additional analyses of the profiles of non-hallucinogenic 5-HT2AR agonists and/or 5-HT2AR positive allosteric modulators may provide a new pathway for 5-HT2AR therapeutics. In this review, we discuss the opportunities and challenges associated with utilizing 5-HT2AR agonists as therapeutics for OUD.

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Section: Psychedelic Pharmacologymentioning

confidence: 99%

Section: Psychedelic Pharmacologymentioning

confidence: 99%

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

Salinsky,

Merritt,

Zamora

et al. 2023

Front. Pharmacol.

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“…After only a single dose, many patients report long-lasting improvements in depression and SUDs, as well as overall well-being for up to a year-a time-span implicating the involvement of cortically mediated long-term memory [3][4][5][6] . Therapeutic-like effects also have been observed in rodent models in many behavioral studies [7][8][9][10][11][12][13][14][15] , enabling the study of the neural mechanisms of psilocybin-enhanced mental health outcomes in mice.…”

Section: Introductionmentioning

confidence: 99%

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Rogers,

Heller,

Corder

2024

Preprint

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The serotonin 2 receptor (5HT2R) agonist psilocybin has demonstrated rapid and long-lasting efficacy across neuropsychiatric disorders characterized by cognitive inflexibility. Psilocybin may accomplish this by inducing rapid and stable dendritic plasticity. However, the impact of psilocybin on patterns of neural activity underlying sustained changes in cognitive and behavioral flexibility has not been characterized. To test the hypothesis that psilocybin enhances behavioral flexibility by rapidly and persistently altering activity in cortical neural ensembles, we performed longitudinal single-cell calcium imaging in the retrosplenial cortex across a five-day trace fear learning and extinction assay. Leveraging tensor component analysis to identify neurons that modulate activity on multiple temporal scales, we found that a single-dose of psilocybin induced cortical ensemble turnover between fear learning and extinction days while oppositely modulating activity in fear- and extinction- active neurons. The extent of suppression of fear-active neurons and recruitment of extinction-active neurons were both predictive of psilocybin-enhanced fear extinction. These results both align with hypotheses that psilocybin enhances behavioral flexibility by recruiting new populations of neurons and introduce a new mechanism involving the suppression of fear-active populations in the retrosplenial cortex.

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“…Preclinical studies in animal models are critical for advancing the understanding of the behavioural and pharmacological mechanisms underlying the therapeutic effects of psilocybin 26 , with evidence converging on increased neuroplasticity as a key driver of beneficial outcomes 27, 28 . Unfortunately, efforts in this space have focused largely on traditional assays of depression-related behaviour in rodents 29 , with variable findings of either improvements 30 or no effects 31 , dependent on the assay or animal model used 32 .…”

Section: Introductionmentioning

confidence: 99%

Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms

Conn,

Milton,

Huang

et al. 2023

Preprint

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Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2aandHtr1a, respectively), and a further reduction in the abundance ofHtr2atranscripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

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Preclinical perspectives on the mechanisms underlying the therapeutic actions of psilocybin in psychiatric disorders

Cited by 11 publications

References 117 publications

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

μ-opioid receptor agonists and psychedelics: pharmacological opportunities and challenges

Psilocybin-enhanced fear extinction linked to bidirectional modulation of cortical ensembles

Psilocybin prevents activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms

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