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

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## 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 the DSM-V characteristic that environmental stimuli associated with a stressor or drug
use can precipitate symptoms of each disorder. Repeated drug use or acute stress produce enduring changes
in synaptic plasticity in a circuit containing the nucleus accumbens and ventral pallidum. Also, stress- and drug-
conditioned cues elicit drug seeking and stress behaviors by inducing transient synaptic plasticity at these
synapses. The first overarching hypothesis in our Merit renewal is that the neural circuits and cellular
mechanisms mediating conditioned stress contribute strongly to comorbid PTSD and SUDs.
 Cannabis is among the addictive drugs most widely abused by Veterans. During the current Merit Award
funding we used a rat model of cannabis (THC+CBD) self-administration in combination with acute restraint
stress as a rodent surrogate of comorbid PTSD and CUD (Cannabis Use Disorder). By associating an odor
with acute stress we studied the behavioral and neurobiological effects of conditioned stress and how drug use
alters those effects. We discovered that cannabis use changes and appears to exacerbate conditioned stress
behaviors. Given the high comorbidity between PTSD and CUD in Veterans, this is a clinically relevant
discovery that is the focus of the renewal Merit application. We are proposing to explore the neurbiological
underpinnings of how cannabis use is changing responses to stress-conditioned cues. We will focus on a brain
circuit known to be critical for conditioned responses, the projection from the nucleus accumbens to ventral
pallidum. Discoveries during the current Merit Award revealed that quantifying stress-cue induced synaptic
changes in the canonical pre- and postsynapse of the accumbens was insufficient to understand the
behaviorally relevant transient plasticity produced by stress cues. Accordingly, will also quantify signaling in the
protein-rich extracellular matrix 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, and the second
overarching hypothesis of the Merit renewal is that cannabis use alters tetrapartite synapses in the accumbens
to pallidum pathway in a manner that changes cue-induced stress responses.
 The proposed Aim 1 characterizes the behavioral and syna...

## Key facts

- **NIH application ID:** 10690184
- **Project number:** 2I01BX004727-05
- **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:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-08-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690184

## Citation

> US National Institutes of Health, RePORTER application 10690184, Neuroadaptation produced by acute PTSD-like stress create vulnerability for cannabis addiction (2I01BX004727-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10690184. Licensed CC0.

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