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.
Classic psychedelics may treat mood and substance use disorders by reversing learned helplessness, a well-studied phenomenon across mammals. The neural circuits underlying resilience to learned helplessness, including the dorsal raphe nucleus, overlap with those activated by psychedelics. Preclinical data show psychedelics improve performance in rodent behavioral despair tasks, supporting this hypothesis. The learned helplessness paradigm offers a robust model for investigating psychedelic mechanisms across behavioral, neurobiological, and clinical levels, potentially explaining transdiagnostic therapeutic effects.
Psilocybin is being studied as a treatment for psychiatric and neurologic conditions, but there is limited comprehensive data on its cardiovascular safety. Current clinical trials typically exclude people with blood pressure of 140/90 mmHg or higher, a cutoff set conservatively without strong empirical evidence.
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.