# Neuroadaptation produced by acute PTSD-like stress create vulnerability for cannabis addiction

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2022 · —

## Abstract

The incidence of post-traumatic stress disorder (PTSD) among combat-experienced Veterans is ~20%,
which is substantially larger than in the general population (~3.5%). Moreover, 40-50% of Veterans suffering
PTSD are also diagnosed with substance use disorders (SUDs). Patients with comorbid PTSD and SUDs have
greater drug use severity and show poorer treatment outcomes than patients diagnosed with either PTSD or
SUDs alone. This special need of returning combat Veterans is largely unaddressed by preclinical research.
PTSD and SUDs share in common the DSM-V characteristic that environmental stimuli associated with a
stressor or drug use can precipitate symptoms of the disorder. Conditioned drug cravings involve activation of
a circuit containing the prefrontal cortex and nucleus accumbens, and repeated drug use produces enduring
changes in synaptic plasticity in the accumbens. Also, drug-conditioned cues elicit drug seeking in animal
models of relapse by inducing transient synaptic plasticity at these synapses. We recently published and
present further new data that a single episode of acute restraint stress in rats produces long-lasting (>3 weeks)
changes in accumbens synapses that parallel the changes produced by addictive drugs. The overarching
hypothesis in our proposal is that cues predicting stress or drug delivery employ the same cortico-accumbens
mechanisms to elicit drug seeking and conditioned stress responding, and that these mechanisms underlie
comorbid PTSD and SUDs.
 Cannabis is among the addictive drugs most widely abused by Veterans. We recently developed a model of
cannabis self-administration and cue-induced drug seeking in rats that uses a combination of two constituents
of cannabis, 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We propose to use THC+CBD self-
administration and reinstated drug seeking in combination with acute restraint stress to evaluate how cannabis
use and conditioned stress interact through accumbens synaptic plasticity to promote stress-induced drug
seeking. Our investigation will utilize recent discoveries showing that quantifying synaptic changes in the
canonical pre- and postsynapse is insufficient to understand the transient plasticity produced by drug cues.
Accordingly, we will also quantify signaling in the protein-rich extracellular matrix (ECM) that surrounds the
synapse, and changes in perisynaptic astroglial processes that regulate synaptic transmission through the
patterned expression of proteins adjacent to the synaptic cleft. Together, these four synaptic compartments are
referred to as the tetrapartite synapse.
 The three proposed Specific Aims will be sequentially engaged. Aim 1 characterizes the behavioral and
synaptic effects of conditioned stress using the defensive burying model of stress responding that will allow
correlations to be evaluated between stress responding and measures of tetrapartite synaptic plasticity. Aim 2
uses the information garnered in Aim 1 to investigate the ...

## Key facts

- **NIH application ID:** 10477266
- **Project number:** 5I01BX004727-04
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Peter W Kalivas
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477266

## Citation

> US National Institutes of Health, RePORTER application 10477266, Neuroadaptation produced by acute PTSD-like stress create vulnerability for cannabis addiction (5I01BX004727-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10477266. Licensed CC0.

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