Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

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.

The Effects of Tryptamine Psychedelics in the Brain: A meta-Analysis of Functional and Review of Molecular Imaging Studies

“…In line with this, previous studies indicated the effects of tryptamine psychedelics on dimensions related to healthy social functioning such as increased emotional empathy and prosocial behaviour ( Dolder et al, 2016 ; Pokorny et al, 2017 ; Mason et al, 2019 ; Uthaug et al, 2021 ), changes in personality traits agreeableness ( Netzband et al, 2020 ) and compassion ( Apud Peláez, 2020 ), as well as feelings of connection to others ( Watts et al, 2017 ). A recent study in mice reported that repeated administration of low doses of LSD promoted social behaviour by potentiating 5-HT2AR and AMPA receptor neurotransmission in the mPFC via an increasing phosphorylation of the mTORC1 ( de Gregorio et al, 2021 ).…”

Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

“…Psychedelic compounds alter social cognitive processes (Table 2) and studies in rodents are beginning to elucidate the underlying mechanistic pathways. A study in male mice showed that repeated doses of LSD (30 µg/kg, daily for 7 days), but not a single dose, resulted in more time interacting with a stranger mouse in the direct social interaction test, associated with potentiation of mPFC excitatory transmission via 5-HT2A and AMPA receptors and via an increasing phosphorylation of the mTORC1 protein (269). Moreover, the inactivation of mPFC glutamate neurotransmission impaired social behavior and negated the prosocial effects of LSD (269).…”

“…A study in male mice showed that repeated doses of LSD (30 µg/kg, daily for 7 days), but not a single dose, resulted in more time interacting with a stranger mouse in the direct social interaction test, associated with potentiation of mPFC excitatory transmission via 5-HT2A and AMPA receptors and via an increasing phosphorylation of the mTORC1 protein (269). Moreover, the inactivation of mPFC glutamate neurotransmission impaired social behavior and negated the prosocial effects of LSD (269). Another study suggested that psilocybin attenuated some of the sociability deficits in a prenatal valproic acid mouse model of autism (270).…”

Psychedelics, Sociality, and Human Evolution

“…Recent work with rodents has unveiled a mechanism of action potentially underlying the prosocial effects of psychedelics. De Gregorio et al (2021b) have demonstrated that repeated administration of low doses of LSD in mice enhances social interaction by potentiating 5-HT 2A and AMPA receptor neurotransmission in the medial prefrontal cortex via an increasing phosphorylation of the mTORC1 (a protein involved in the modulation of social behavior). Moreover, psilocybin has been found to increase striatal dopamine concentrations in humans, a mechanism partly underlying euphoria and depersonalization phenomena ( Vollenweider et al, 1999 ).…”