Anti-anxiety and hallucination-like effects of psychedelics mediated by distinct neural circuits

Psychedelics can produce both anti-anxiety and hallucination-like effects through different neural circuits, according to a mouse study linked to a Science paper. Researchers used the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) and measured anxiety-like behavior with the elevated plus maze and marble burying. Six hours after dosing, mice still showed reduced anxiety-like behavior, while head twitches tied to hallucination-like effects had disappeared. Using a molecular tagging tool (scFLARE2) to identify DOI-activated neurons in the medial prefrontal cortex, then reactivating those cells with optogenetics, the team showed that targeting the DOI-responsive network can drive anti-anxiety-like behavioral changes while the hallucinogenic-like signatures were no longer present. Single-nucleus RNA sequencing was used to characterize neuron types in the network, supporting the idea that therapeutic effects may be decoupled from hallucinogenic effects by selecting specific circuitry rather than only changing chemical structure.