Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission
Danilo de Gregorio, Jelena Popić, Justine P. Enns, Antonio Inserra, Agnieszka Skalecka, Athanasios Markopoulos, Luca Posa, Martha López-canul, Qianzi He, Christopher K. Lafferty, Jonathan P. Britt, Stefano Comai, Argel Aguilar-Valles, Nahum Sonenberg, Gabriella Gobbi
Proceedings of the National Academy of Sciences January 25, 2021 DOI: 10.1073/pnas.2020705118 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Multidisciplinary experimental study with in vivo electrophysiology, optogenetics, behavioral paradigms, molecular biology, and conditional knockout mice Peer reviewed |
|---|---|
| Population | Male mice |
| Intervention | LSD |
| Dose | 30 μg/kg |
| Duration | 7 days |
| Topics | Neuroplasticity LSD |
| Keywords | Excitatory postsynaptic potential Neurotransmission Ampa receptor Glutamatergic Pharmacology Long-term potentiation Mtorc1 |
| Citations | 137 |
| Key findings | LSD enhances social behavior by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTORC1 signaling in glutamatergic neurons. |
Abstract
Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT 2A , but not N -methyl-D-aspartate (NMDA) and 5-HT 1A , synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons ( Raptor f/f :Camk2alpha-Cre ), the prosocial effects of LSD and the potentiation of 5-HT 2A /AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC ( Raptor f/f :Gad2-Cre ), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT 2A /AMPA receptors and mTOR signaling. The activation of 5-HT 2A /AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex Human embryonic kidney 293 cells stably expressing 5-HT2ARs; wild-type and 5-HT2AR... | 2003 | Experimental study | |
| Evidence for a central 5‐hydroxytryptamine receptor stimulation by lysergic acid diethylamide Rats | 1968 | Experimental study | |
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Lysergic Acid Diethylamide- and Mescaline-Induced Attenuation of the Effect of Punishment in the Rat Rats | 1976 | Experimental study |
Citations in the library
Cited by 115
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
- Pharmacological, neural, and psychological mechanisms underlying psychedelics: a critical review Neuroscience & Biobehavioral Reviews September 1, 2022
- Psychedelics and Other Psychoplastogens for Treating Mental Illness Frontiers in Psychiatry October 4, 2021
- Shared and Distinct Brain Regions Targeted for Immediate Early Gene Expression by Ketamine and Psilocybin ACS Chemical Neuroscience January 11, 2023
and 110 more in the library
Cites 23
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects Biological Psychiatry November 29, 2014
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
and 18 more in the library