Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI.
Praachi Tiwari, Pasha A. Davoudian, Darshana Kapri, Ratna Mahathi Vuruputuri, Lindsay A Karaba, Mukund Sharma, Giulia Zanni, Angarika Balakrishnan, Pratik R Chaudhari, Amartya Pradhan, Shital Suryavanshi, Kevin G Bath, Mark S Ansorge, Antonio Fernandez-Ruiz, Alex C. Kwan, Vidita A Vaidya
Neuron November 20, 2024 DOI: 10.1016/j.neuron.2024.08.016 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | 2 5-dimethoxy-4-iodoamphetamine (DOI) |
| Topics | Anxiety Serotonin |
| Keywords | 2,5-dimethoxy-4-iodoamphetamine Ca1 Fast-spiking cells Subiculum |
| Citations | 26 |
| Key findings | 5-HT2A receptors on PV-positive fast-spiking interneurons in the ventral hippocampus CA1/subiculum are required for the anxiolytic effect of DOI. |
Abstract
There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT2A receptors. Restoration of 5-HT2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 14
- A multi-institutional investigation of psilocybin’s effects on mouse behavior bioRxiv (Cold Spring Harbor Laboratory) April 9, 2025
- LSD's rapid antidepressant effects are modulated by 5-HT2B receptors. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie July 16, 2025
- Sex-specific role of the 5-HT2A receptor in psilocybin-induced extinction of opioid reward. Nature Communications November 20, 2025
- The ABCs of psychedelics: a preclinical roadmap for drug discovery. TIPS - Trends in Pharmacological Sciences August 28, 2025
- Pretreatment with the psychedelic DOI mitigates LPS-induced hippocampal inflammation and behavioral impairments in mice BMC Neuroscience March 24, 2026
and 9 more in the library
Cites 36
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Pilot Study of Psilocybin Treatment for Anxiety in Patients With Advanced-Stage Cancer Archives of General Psychiatry September 7, 2010
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
and 31 more in the library