# Reversing Cocaine-induced Impairments in the NAc with Controllable Stressors

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2020 · $354,954

## Abstract

Project Summary / Abstract
Drug addiction is a chronically relapsing disorder that often has devastating consequences for the addicted
person and society as a whole. In particular, during periods of drug abstinence, drug-associated stimuli or
general feelings of stress may elicit powerful feelings of craving in drug-dependent individuals. Indeed, stress
is a particularly potent trigger because, unlike drug cues (e.g., paraphernalia) and contexts (i.e., places where
drugs are obtained or used) which can be avoided, stress is unavoidable in non-drug contexts such as work,
family, or finances. In most conditions, these stressful encounters are aversive and unavoidable, and can
create a heightened anxiety state that addicted individuals attempt to alleviate by relapse to a drug-taking
episode. However, in contrast to these inescapable stressors, in some situations it is possible to have control
over an aversive situation. These controllable stressors, while still aversive, nonetheless have been shown to
endow subjects with trans-situational resilience against future stressors. In an animal model of stressor
controllability, rats can rotate a wheel to terminate an aversive tailshock (escapable shock; ES). Physically
yoked animals receive the same shocks as the ES subjects, but are unable to control the experience, and thus
perceive the shock as inescapable (IS). After a single ES session, rats show decreased fear reactivity in fear
conditioning, conditioned social defeat compared to IS subjects and even non-stressed controls. While much is
known about how uncontrollable stressors can potentiate drug-taking and relapse, little is known about whether
ES experience may reverse these negative consequences. Here we report that while rats with a history of
repeated cocaine self-administration display impaired neural signaling in the NAc as well as poor acquisition of
higher-order associations, these deficits can be prevented or reversed by a single ES experience during the
abstinence period, while also decreasing drug seeking in extinction. These control-related effects may derive
from functionally overlapping set of circuits between the NAc, prefrontal cortex (PFC) and ventral tegmental
area (VTA). This set of structures is known to support motivated learning and stress-induced drug relapse, and
while PFC is critical for controllabilty, less is known about whether NAc or VTA also contribute to these
processes. To fully characterize this phenomenon, I will first identify how neural signaling in the PFC encodes
control-related information and whether this is related to recovered function in motivated learning and
resistance to drug relapse. Next, we will use optogenetics to determine the necessity of PFC-to-NAc pathways
in establishing the neuroprotective-like effects of control on subsequent learning and relapse. Finally, I will use
TH::cre rats to determine whether dopamine signaling is critical for the acquisition and later expression of
control-related b...

## Key facts

- **NIH application ID:** 9994857
- **Project number:** 5R01DA044980-03
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Michael Saddoris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,954
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994857

## Citation

> US National Institutes of Health, RePORTER application 9994857, Reversing Cocaine-induced Impairments in the NAc with Controllable Stressors (5R01DA044980-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9994857. Licensed CC0.

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