Journal of Neuroscience
April 15, 1997
Vidita A Vaidya, Gerard J. Marek, George K. Aghajanian et al.
482 citations
A hallucinogenic 5-HT2A/2C receptor agonist, but not a 5-HT1A receptor agonist, differentially regulated BDNF mRNA levels in rat brain. In the hippocampus, it decreased BDNF mRNA in the dentate gyrus granule cell layer without affecting CA subfields. In neocortical areas (but not piriform cortex), it dramatically increased BDNF mRNA. These effects were blocked by a selective 5-HT2A, but not 5-HT2C, receptor antagonist. Stress-induced downregulation of BDNF mRNA in hippocampus was blocked by pretreatment with ketanserin, a 5-HT2A/2C antagonist, suggesting 5-HT2A receptors mediate that effect. The findings suggest hallucinogenic 5-HT2A agonists may alter synaptic strength in hippocampus and neocortex, potentially mediating behavioral effects.
Frontiers in Molecular Neuroscience
December 24, 2021
Lynette A. Desouza, Madhurima Benekareddy, Sashaina E. Fanibunda et al.
46 citations
The hallucinogenic compound DOI, which activates the 5-HT2A receptor, rapidly increases the expression of several genes linked to neuronal plasticity in rat cortical neurons and neocortex. This upregulation involves the transcription factor CREB, which becomes phosphorylated through MAP kinase and CaMKII signaling pathways. DOI enhanced CREB binding to specific gene promoters (Arc, Bdnf1, Cebpb, cFos) but not others (Egr1, Egr2). In mice lacking CREB, DOI-induced expression of Arc, cFos, and Cebpb was significantly reduced. The findings suggest that serotonergic psychedelics may recruit CREB to drive rapid psychoplastogenic effects, similar to slower-acting antidepressants.
Neuron
November 20, 2024
Praachi Tiwari, Pasha A. Davoudian, Darshana Kapri et al.
26 citations
The serotonergic psychedelic DOI reduces anxiety-like behavior by activating 5-HT2A receptors on fast-spiking parvalbumin (PV)-positive interneurons in the CA1/subiculum region of the ventral hippocampus. Experiments combining anatomical, pharmacological, and genetic methods showed that these receptors are necessary for the anxiolytic effect. In vivo recordings revealed that DOI increases the firing rate of PV-positive interneurons, most of which express 5-HT2A receptors. Restoring 5-HT2A receptors specifically in PV-positive cells in a loss-of-function background reinstated DOI's anxiety-relieving effects, identifying these interneurons as a cellular trigger for psychedelic-induced relief of anxiety-like behavior.
Chemical science
June 18, 2025
Rajasree Kundu, Samsuzzoha Mondal, Akshay Kapadia et al.
4 citations
A new fluorescent sensor rapidly enters living cells, neurons, and whole organisms to track the lipid PI(4,5)P2 in real time. Using this probe, the authors show that a hallucinogenic ligand at the serotonin2A receptor depletes PI(4,5)P2 more slowly during the first seconds after binding than a non-hallucinogenic ligand, but its effect lasts longer. This difference in early lipid dynamics may underlie the contrasting behavioral effects of hallucinogenic versus non-hallucinogenic drugs. The sensor offers a tool for observing early molecular events in neuronal signaling.
Progress in neuro-psychopharmacology & biological psychiatry
December 20, 2025
Praachi Tiwari, Vidita A Vaidya
The serotonergic psychedelic DOI alters locomotor activity in rats and mice in a dose-dependent manner, and these changes correlate with anxiety-like behavior in the elevated plus maze. Species- and strain-specific differences emerge: Sprague-Dawley rats and 129S6/SvEv mice show reduced movement at 1 mg/kg DOI, while C57BL/6J mice show increased movement at the same dose. The locomotor modulation, like the anxiety-related effects, depends on the serotonin 2A receptor, as DOI-evoked changes are absent in 5-HT2A receptor knockout mice. These findings underscore the need to account for psychedelics' effects on spontaneous and context-dependent locomotion when interpreting mood-related behaviors in novelty-based approach-avoidance tasks.