# Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2020 · —

## Abstract

PTSD and depression are serious psychiatric disorders afflicting the veteran population, and are frequently
comorbid. Current pharmaco- and psychotherapies are inadequate, and more effective treatments are needed.
Progress has been hampered by a lack of understanding of the neurobiological mechanisms underlying the
pathology and effective treatment of these disorders. We have used chronic unpredictable stress (CUS) to
produce behavioral changes in rats that model several shared dimensions of PTSD and depression, including
a deficit of cognitive flexibility, mediated in the medial prefrontal cortex (mPFC), and a shift from active to
passive coping behavior, which models avoidant coping and withdrawal-related symptoms common to PTSD
and depression. With this paradigm, we have demonstrated therapeutic effects using fear extinction learning
as a novel rat model of exposure therapy. Extinction is an active learning process that modifies expectations of
negative outcome predicted by cues previously paired with an adverse event. Similarly, exposure therapy, a
form of cognitive behavioral therapy, is an active learning process that changes expectations of negative
outcome predicted by cues previously associated with a stressful experience or context. We have shown that
extinction training after CUS reverses the deficits in cognitive flexibility and coping behavior, tested 24 hr after
treatment. We will now use this model to investigate neural mechanisms by which psychotherapy exerts its
beneficial effect. Further, we will compare the mechanisms of extinction therapy with another therapy that has
received recent attention, the NMDA receptor antagonist, ketamine. Ketamine has rapid antidepressant effects
in treatment-resistant patients, and early studies in PTSD also show promise. However, ketamine has many
undesirable qualities that limit its potential utility as a therapeutic agent. If mechanisms for its therapeutic effect
can be identified, especially those shared by a non-pharmacological treatment, it may be possible to target
those mechanisms separately from the ones responsible for its psychotomimetic and addictive properties.
Thus, mechanisms shared by these two very different treatment modalities may represent potentially important
new targets for the development of novel therapeutic strategies. Dysregulation of the mPFC is implicated in the
pathology of PTSD and depression, and the mPFC is a critical component in the circuitry mediating extinction
learning and cognitive flexibility. Thus we will focus our investigations on the mPFC. Activity-dependent protein
synthesis is required for the long-term retention of extinction learning, and signaling pathways involved in
activity-dependent protein synthesis are also activated by ketamine. Also, effects of extinction and ketamine
are evident 24 hr or more after treatment, implying that neural plasticity is involved, as it is in learning. Thus,
our overall hypothesis is that mechanisms underlying the the...

## Key facts

- **NIH application ID:** 9859330
- **Project number:** 5I01BX003512-04
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** ALAN FRAZER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859330

## Citation

> US National Institutes of Health, RePORTER application 9859330, Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats (5I01BX003512-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9859330. Licensed CC0.

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