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.
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.