# The Role of Midbrain to Prelimbic Cortex Glutamatergic projections in Stress-induced Drug Seeking

> **NIH NIH U54** · PONCE SCHOOL OF MEDICINE · 2022 · $78,400

## Abstract

SUMMARY
Despite the recognized correlation between post-traumatic stress disorder (PTSD) and substance use disorder
(SUD), it is unknown how trauma exposure and substance use may interact to alter the probability of an individual
to develop either of these two disorders. Although some studies have revealed participation of the ventral
tegmental area (VTA) and the medial prefrontal cortex (mPFC) in both PTSD and SUD, it is not yet known if the
experience of a traumatic event alters the communication between these two structures in a way that may
increase the risk of acquiring SUD. VTA projections to the mPFC are known to play an important role in the
development of cocaine addiction; and other studies have shown that PTSD pathogenesis induces
neurophysiological changes in the interaction between the amygdala, (VTA), mPFC, and hippocampus.
Recently, studies showed that VTA glutamatergic neurons that co-release dopamine project towards the nucleus
accumbens (NAc) and the prelimbic cortex (PL). Interestingly, VTA-NAc glutamatergic projections are involved
in reward-seeking behavior; but the role of the VTA-PL glutamatergic projections in reward-seeking is still
unknown. The overall goal of this investigation is to understand the mechanisms and adaptations of the brain
when exposed to a traumatic event that leads to increased susceptibility of SUD acquisition. More specifically,
the objective is to elucidate how the VTA glutamatergic projections into the PL are affected by stress and how
this influences cocaine-seeking behavior in male and female rats. Our preliminary behavioral data show that
stress prior to cocaine self-administration increases cocaine acquisition and cocaine-induced reinstatement,
compared with the no-stress group in male rats. Our central hypothesis is that stress will strengthen synaptic
transmission in the VTA-PL glutamatergic synapses, thus enhancing sensitivity to the reinforcing effects of
cocaine and leading to increased cocaine-seeking behavior. To test this hypothesis, we will first evaluate the
behavioral effects of fear conditioning prior to cocaine exposure on acquisition and reinstatement of cocaine-
seeking (Aim 1a). Secondly, we will assess the neurophysiological changes of glutamatergic projections from
the VTA to the PL using optical stimulation with whole cell patch-clamp recordings (ex-vivo) to measure synaptic
changes (AMPA to NMDA ratio) in the VTA-PL glutamatergic synapses from cocaine-exposed rats with or without
prior stress (Aim 1b). These experiments shall reveal how VTA modulates the PL neurons in the presence of
stress and how this in turn, influences the drug seeking behavior.

## Key facts

- **NIH application ID:** 10560233
- **Project number:** 3U54MD007579-37S1
- **Recipient organization:** PONCE SCHOOL OF MEDICINE
- **Principal Investigator:** Richard J. Noel
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,400
- **Award type:** 3
- **Project period:** 1997-08-25 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10560233

## Citation

> US National Institutes of Health, RePORTER application 10560233, The Role of Midbrain to Prelimbic Cortex Glutamatergic projections in Stress-induced Drug Seeking (3U54MD007579-37S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10560233. Licensed CC0.

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