# Neurobiological mechanisms underlying changes in PTSD-like symptoms after cannabis use

> **NIH NIH K99** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $187,152

## Abstract

PROJECT SUMMARY/ABSTRACT: Post-traumatic stress disorder (PTSD) has a high rate of comorbidity with
cannabis use disorder (CUD). Indeed, in veterans diagnosed with CUD, PTSD is the most highly co-occurring
disease. Moreover, patients with comorbid PTSD and CUD have greater drug use severity and show poorer
treatment outcomes than patients diagnosed with either PTSD or CUD alone. Conversely, PTSD is often listed
as a medical condition potentially ameliorated by cannabis use. However, the clinical literature is mixed regarding
the effect of cannabis use on PTSD symptoms, with some earlier studies indicating cannabis use may self-
medicate PTSD and newer literature arguing that it exacerbates PTSD symptoms and reduces treatment
efficacy. Thus, the prevalence of PTSD/CUD comorbidity and the increasing legal status of cannabis in United
States make it imperative to understand the mechanisms whereby cannabis use is potentially promoting or
ameliorating PTSD symptoms. Using acute restraint stress combined with a rat cannabis self-administration
paradigm, I recently found that cannabis use promotes two primary PTSD-like symptoms, avoidance coping
behaviors (immobility in the defensive burying task) and the generalization of stress coping responses to a
neutral stimulus not previously associated with stress exposure. These clinically relevant discoveries are the
foundation for my K99/R00 Pathway to Independence proposal. This proposal aims to identify neurobiological
mechanisms underpinning how cannabis use changes and potentially exacerbates PTSD-like symptoms. During
the K99 portion, I will characterize, in a cell-specific manner, the neuroadaptations induced by the interaction
between stress and cannabis use in the nucleus accumbens core (NAcore). To this end, I will combine in vivo
zymography with confocal microscopy and digital rendering approaches to quantify changes in the tetrapartite
synaptic plasticity, which includes changes in: morphology of D1- and D2-medium spiny neurons (MSNs),
astroglia, and the extracellular matrix (ECM) (Aim 1). I will then use the in vivo single-cell Ca2+ recording from
D1- and D2-MSNs in NAcore, to determine which cell type and what patterns of activity are associated with the
exacerbating effects of cannabis use on stress responses (Aim 2). In the R00 portion, I will apply my K99 training
to study how stress and cannabis affect the tetrapartite synaptic plasticity in ventral pallidum (VP), a primary
accumbens output nucleus that translates rewarding and aversive stimuli into behavioral responses. I will assess
the signaling between ECM, astrocyte and GABAergic neurons (VPGABA), as well as the expression of
perineuronal nets (PNNs) following acute stress and cannabis use (Aim 3a). I will then evaluate the specific role
of PNNs in the altering effects of cannabis use on stress responses (Aim 3b). Finally, I will use changes in
intracellular Ca2+ to determine if exposure to stress-conditioned stimuli or neutral stimuli c...

## Key facts

- **NIH application ID:** 10885385
- **Project number:** 1K99DA058761-01A1
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Ritchy Hodebourg
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $187,152
- **Award type:** 1
- **Project period:** 2024-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885385

## Citation

> US National Institutes of Health, RePORTER application 10885385, Neurobiological mechanisms underlying changes in PTSD-like symptoms after cannabis use (1K99DA058761-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10885385. Licensed CC0.

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