# Prefrontal-to-accumbal projections mediate stress-modulated drug seeking

> **NIH NIH F31** · UNIVERSITY OF COLORADO · 2020 · $37,654

## Abstract

PROJECT SUMMARY
 Even after periods of abstinence, stress can potently trigger drug cravings and induce relapse.
Uncontrollable stress prior to exposure to drug-associated cues (e.g. paraphernalia) can generate enhanced
vulnerability to relapse. However, a stressor over which an animal can acquire control produces vastly different
behaviors outcomes. These stressors, while still aversive, have been shown to endow animals with resilience
against future stressors, even when these stressors occur in different contexts or require unique actions. In an
animal model of stressor controllability, rats can turn a wheel to escape tail-shock (escapable stress; ES).
However, yoked animals that receives physically identical shock have no such perception of control
(inescapable stress; IS). After a single session of repeated trials, ES-experienced animals express reduced
neophobia and hypervigilance, similar to stress-naïve home-cage controls, while there IS counterparts exhibit
heightened states of anxiety. Moreover, cocaine-experienced animals that have learned to control this stressor
exhibit accelerated learning to extinguish cocaine-seeking behaviors. This suggests that stressful experiences
may produce opposing effects on drug-seeking, dependent upon whether the stressor was controllable or not.
It is unknown whether these bi-directional effects reflect distinct changes in the neural circuits responsive to
triggers of drug craving, such as drug-associated cues. Notably, cue-reinforced drug-seeking is progressively
enhanced over the first 30 days of cocaine abstinence, and this incubation of craving is thought to reflect
changes in prelimbic cortex (PL) to nucleus accumbens (NAc) core connectivity. Therefore, the proposed
experiments will explore whether controllable (ES) and uncontrollable (IS) stress experiences produce distinct
effects on PLàNAc core projections over the course of abstinence from either cocaine or sucrose. In Aim 1,
we will use fiber photometry of GCaMP6f transients to record calcium activity from these projections as
animals are exposed to cues (i.e. lights) previously associated with administration. In Aim 2, we will then
determine whether these PLàNAc core projections are engaged in and necessary for the learning of stressor
controllability, such that optogenetic inhibition prevents later expression of trans-situational resilience. The
proposed experiments will therefore delineate the role of PLàNAc core neurons in the response to stress
during abstinence and elucidate how stress-induced changes within these projections modulates drug-seeking
behavior.

## Key facts

- **NIH application ID:** 9970152
- **Project number:** 5F31DA049505-02
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Kayla Ann Siletti
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,654
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9970152

## Citation

> US National Institutes of Health, RePORTER application 9970152, Prefrontal-to-accumbal projections mediate stress-modulated drug seeking (5F31DA049505-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9970152. Licensed CC0.

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