Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission
Contributed by Nahum Sonenberg, November 10, 2020 (sent for review October 5, 2020; reviewed by Marc G. Caron and Mark Geyer)
Significance
Social behavior (SB) is a fundamental hallmark of human interaction. Repeated administration of low doses of the 5-HT2A agonist lysergic acid diethylamide (LSD) in mice enhances SB by potentiating 5-HT2A and AMPA receptor neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1, a protein involved in the modulation of SB. Moreover, the inactivation of mPFC glutamate neurotransmission impairs SB and nullifies the prosocial effects of LSD. Finally, LSD requires the integrity of mTORC1 in excitatory glutamatergic, but not in inhibitory neurons, to produce prosocial effects. This study unveils a mechanism contributing to the role of 5-HT2A agonism in the modulation of SB.
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-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, 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 (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/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 (Raptorf/f:Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/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.
Data Availability
All study data are included in the article and supporting information.
Acknowledgments
We thank Annie Sylvestre, Annik Lafrance, Annamaria Kiss, Isabelle Harvey, and Anmol Nagpal for technical assistance, and the NeuroSphere Team (Laura Rivest-Khan and Dr. Marc Lussier). D.D.G. was a recipient of Fond Recherche Québec-Santé (FRQS) and a Canadian Institutes for Health Research (CIHR) postdoctoral fellowship. L.P. was a recipient of a FRQS PhD fellowship. M.L.-C. was a recipient of a Faculty of Medicine of McGill University/Ferring postdoctoral fellowship. This work was supported by Grant 436986 from the CIHR, the Quebec Network for Suicide, Mood Disorders, and Related Disorders (RQSHA, FRQS Grant 268065).
Supporting Information
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Cover image: Pictured is a puppy that received a rabies vaccine at a static point vaccination clinic in Blantyre city, Malawi. Between 2015 and 2017, Stella Mazeri et al. recruited staff to annually vaccinate around 35,000 dogs in Blantyre city via fixed locations and door-to-door vaccination clinics. Because door-to-door vaccination is more expensive and labor-intensive than static point vaccination clinics, the authors redesigned the annual vaccination campaign to encourage static clinic attendance. Increasing the number of static clinics, enhancing public awareness of the vaccination campaign, and using a rapid response vaccination team to target areas of low vaccination coverage resulted in the vaccination of near-identical numbers of dogs in 2018 as in previous years, but in a shorter period with fewer staff members, while achieving more than 70% vaccination coverage of all dogs in Blantyre city. See the article by Mazeri et al., e2003722118. Image credit: Mission Rabies.
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Copyright © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Data Availability
All study data are included in the article and supporting information.
Submission history
Published online: January 25, 2021
Published in issue: February 2, 2021
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Acknowledgments
We thank Annie Sylvestre, Annik Lafrance, Annamaria Kiss, Isabelle Harvey, and Anmol Nagpal for technical assistance, and the NeuroSphere Team (Laura Rivest-Khan and Dr. Marc Lussier). D.D.G. was a recipient of Fond Recherche Québec-Santé (FRQS) and a Canadian Institutes for Health Research (CIHR) postdoctoral fellowship. L.P. was a recipient of a FRQS PhD fellowship. M.L.-C. was a recipient of a Faculty of Medicine of McGill University/Ferring postdoctoral fellowship. This work was supported by Grant 436986 from the CIHR, the Quebec Network for Suicide, Mood Disorders, and Related Disorders (RQSHA, FRQS Grant 268065).
Authors
Competing Interests
Competing interest statement: G.G. is a consultant at Diamond Therapeutics Inc, Toronto, ON, Canada. G.G. and D.D.G. are inventors of a provisional patent regarding the use of LSD.
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