Proceedings of the National Academy of Sciences
January 25, 2021
Danilo de Gregorio, Jelena Popić, Justine P. Enns et al.
137 citations
Repeated doses of LSD (30 μg/kg daily for 7 days) increase social behavior in male mice without producing antidepressant or anxiety-reducing effects. The prosocial effect requires the integrity of mTORC1 in excitatory glutamatergic neurons of the medial prefrontal cortex (mPFC), as shown by optogenetic inhibition and conditional knockout experiments. LSD potentiates AMPA and 5-HT2A synaptic responses in the mPFC and increases phosphorylation of Akt and mTOR, but does not affect NMDA or 5-HT1A responses. In mice lacking Raptor in GABAergic neurons, LSD still promotes social behavior. The findings suggest that 5-HT2A/AMPA/mTORC1 signaling in mPFC excitatory neurons mediates LSD's prosocial effects, offering a potential target for treating social deficits in autism and social anxiety.
International Journal of Molecular Sciences
November 23, 2016
Danilo de Gregorio, Stefano Comai, Luca Posa et al.
125 citations
LSD produces hallucinogenic and psychotic-like effects through a complex mechanism involving multiple neurotransmitter systems. The primary action occurs in the Dorsal Raphe via the serotonergic system, where LSD acts as a partial agonist at 5-HT2A receptors and an agonist at 5-HT1A receptors. At higher doses, it also stimulates dopamine D2 receptors, Trace Amine Associated Receptor 1 (TAAR1), and 5-HT2A in the Ventral Tegmental Area. This pleiotropic mechanism, engaging serotonergic, dopaminergic, and glutamatergic pathways, makes LSD-induced psychosis a useful preclinical model for testing novel antipsychotic drugs, especially those targeting dual serotonergic and dopaminergic systems or TAAR1 receptors. More human studies are needed to clarify these mechanisms.
The International Journal of Neuropsychopharmacology
July 23, 2020
Danilo de Gregorio, Joshua Dean Conway, Martha-Lopez Canul et al.
39 citations
Chronic exposure to a low dose of THC (1 mg/kg) during adolescence in rats leads to depressive-like behaviors (increased immobility in the forced swim test and anhedonia in the sucrose preference test) and anxiety-like behavior (fewer open-arm entries in the elevated plus maze). Adult exposure also produces anxiety but not depressive-like behaviors. Both adolescent and adult THC exposure reduce the activity of serotonin neurons in the dorsal raphe, while noradrenergic neurons in the locus coeruleus remain unaffected. These findings suggest that the serotonin system is vulnerable to chronic low-dose THC, and that adolescents are particularly susceptible to THC-induced depressive effects.
Cell
April 30, 2026
Hermany Munguba, Anisul Arefin, Ryota Hasegawa et al.
4 citations
Ketamine's rapid antidepressant effects depend on mu-opioid receptors (MORs) located on somatostatin-expressing interneurons in the medial prefrontal cortex. Chronic stress causes these interneurons to become hypertrophic, leading to excessive inhibition of pyramidal neurons, a disruption that ketamine reverses. By identifying GPCRs enriched in these interneurons through RNA sequencing, the authors validate several antidepressant targets and show that activating multiple GPCRs synergistically produces potent antidepressant-like effects with fewer side effects. This approach offers a general strategy for discovering GPCR-based treatments for brain disorders.