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.
Progress in Neuro-Psychopharmacology and Biological Psychiatry
October 1, 2025
Brandon Richardson, Antonio Inserra, Michael Pileggi et al.
2 citations
Psilocybin and lisuride both activate 5-HT2A receptors, but only psilocybin triggers the head twitch response (HTR) in mice, a proxy for hallucinogenic activity. In adult male C57BL/6N mice, psilocybin (0.3–3 mg/kg) inhibited serotonin neuron firing in the dorsal raphe nucleus via 5-HT2A receptors, while lisuride (0.1–0.5 mg/kg) did not. Both drugs reduced dopamine neuron firing in the substantia nigra, but lisuride's effect was more sensitive to 5-HT2A antagonism. Psilocybin elicited HTR; lisuride did not. Only high-dose lisuride reduced immobility in the forced swim test. Both drugs reduced locomotion in open field and elevated plus maze tests. Principal component analysis separated the drug effects, indicating distinct neurobiological pathways: psilocybin produces psychedelic-like, serotonin-dominant effects, while lisuride displays dopamine-linked improvements in coping behavior.
The International Journal of Neuropsychopharmacology
August 1, 2025
B. D. Richardson, Marco Pileggi, Thomas Prudhomme et al.
Psilocybin and lisuride both bind to 5-HT2A receptors, but only psilocybin produces hallucinogenic effects. In adult male mice, both drugs inhibited serotonin neuron activity in the dorsal raphe nucleus and dopamine neuron firing in the substantia nigra. A 5-HT2A antagonist blocked psilocybin's serotonin inhibition but not lisuride's, suggesting different mechanisms. Only lisuride showed an antidepressant-like effect at the highest doses. Psilocybin, but not lisuride, elicited head-twitch responses, and lisuride blocked those induced by psilocybin. Both drugs reduced locomotion. The findings indicate lisuride has antidepressant and sedative effects without hallucinogenic action, likely due to its distinct effects on serotonin and dopamine neurons.
Alzheimer's & dementia : the journal of the Alzheimer's Association
August 1, 2024
Felipe C Ribeiro, Danielle Cozachenco, Elentina K Argyrousi et al.
The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) activates signaling pathways (ERK1/2, mTOR, S6K1) in the hippocampus, rescuing long-term potentiation and memory deficits in two mouse models of Alzheimer's disease: mice infused with amyloid-β oligomers and aged APP/PS1 mice. The rescue depends on ERK signaling. HNK also corrects aberrant transcription in APP/PS1 mice. These results suggest HNK could be a therapeutic approach for Alzheimer's disease.