# Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments

> **NIH VA I01** · SOUTHEAST LOUISIANA VETERANS HEALTH CARE · 2020 · —

## Abstract

One debilitating mental health problem among veterans is post-traumatic stress disorder
(PTSD), which is an anxiety disorder (PTSD) and develops following the experience of life-
threatening psychological trauma. Individuals with PTSD have reduced circulating levels of
endocannabinoids (eCB) including 2-AG. Since disruption of 2-AG signaling leads to mood
disorders, impaired memory extinction and enhanced pain, the ability to reverse the stress-
induced change in 2-AG production/degradation holds great potential for the treatment of PTSD.
Given the importance of 2-AG signaling in the stress response and associative fear learning, an
understanding of how stress produces a lasting decrease in 2-AG levels is needed to bridge
the knowledge gap that exists between traumatic stress and the associated reduction in 2-AG
content. Exposure of rodents to natural predator odors causes psychological stress, leading to
enhanced associative fear learning and thus has been used to model several aspects of PTSD.
We have previously shown that fox urine exposure produced a lasting increase in excitatory
synaptic transmission via the activation of adrenergic receptors in the mouse cerebellum. This
brain region is required for the innate response to predator odor and for the consolidation of fear
memory. Our pilot data show that predator odor exposure reduced 2-AG signaling in the
cerebellum and this stressor abolished A-type K currents in inhibitory interneurons. Therefore
our central hypothesis is that predator odor stress enhances excitability of GABAergic
interneurons and thereby reduces 2-AG signaling, thus pharmacological interventions that
inhibit 2-AG degradation and reduce neuronal excitability would reverse the stress-induced
decrease in 2-AG levels. In Aim 1, we will determine whether a psychological stress reduces 2-
AG tone by increasing 2-AG degradation or by reducing 2-AG production. Aim 2 will test the
hypothesis that emotional stress reduces 2-AG signaling by increasing inhibitory interneuron
activity. We will test whether several FDA approved drugs that reduce neuronal activity can
reverse the stress-induced change. Because the proposed study investigates a new mechanism
underlying the regulation of 2-AG metabolism by psychological stress, it could suggest novel
treatment strategies for PTSD and new therapeutic targets.

## Key facts

- **NIH application ID:** 9815330
- **Project number:** 5I01BX003893-02
- **Recipient organization:** SOUTHEAST LOUISIANA VETERANS HEALTH CARE
- **Principal Investigator:** Siqiong June Liu
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815330

## Citation

> US National Institutes of Health, RePORTER application 9815330, Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments (5I01BX003893-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815330. Licensed CC0.

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