# Role of Extinction in Circuit-Specific Modulation of Motivation and Mood in Cocaine Addiction

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $364,500

## Abstract

PROJECT SUMMARY
 Drug addiction is a serious and prolific mental illness involving persistent relapse despite sincere efforts to
abstain. Extinction training has been used as a therapeutic method to reduce drug craving and relapse,
although with limited efficacy due to an inability to fully capture contextual aspects unique to individual drug
users. The identification of extinction-induced modifications in distinct brain circuits could lead to better
neurostimulation approaches to treat drug addiction. This research studies modification of specific neural
circuits by the extinction of self-administration behavior in a rat model of cocaine addiction. Our previous data
indicate that extinction training enhances excitatory synaptic input to nucleus accumbens (NAc) shell neurons,
and this effect attenuates psychomotor sensitization and relapse to cocaine-seeking behavior. The primary
excitatory inputs to the NAc shell originate in the medial prefrontal cortex (PfC), basolateral amygdala (BlA)
and ventral hippocampus (VH). Using an optogenetic low frequency stimulation approach to selectively
depotentiate excitatory synaptic input emanating from these regions, this research will identify the specific
source(s) of extinction-induced neuroplasticity in the NAc shell (Aim I), and study the role of this circuit-specific
neuroplasticity in extinction-induced attenuation of sensitization and relapse behaviors (Aim II). Previous data
also suggest that extinction of cocaine self-administration may reverse negative mood effects produced by
chronic cocaine use. Thus, studies will determine the role of circuit-specific neuroplasticity in extinction-
induced antidepressive efficacy (Aim III).
 Studies in Aim 1 will employ optogenetics to study the extinction circuits responsible for 1) extinction-
induced synaptic trafficking of AMPA GluA receptor subunits, 2) extinction-induced enhancement in excitatory
synaptic currents and 3) determine the direct and/or indirect NAc output neurons modified by extinction.
Experiments in Aim II will determine the role of extinction-potentiated circuits in 4) extinction-induced reversal
of locomotor sensitization and 5) extinction-induced attenuation of context- and cocaine-primed reinstatement
of cocaine-seeking behavior. Experiments in Aim III will investigate the role of extinction-specific
neuroplasticity in reversing negative mood effects in tests of 6) dysphoria in cocaine-conditioned place
aversion, 7) learned helplessness/behavioral despair in forced swim tests and 8) anhedonia in sucrose
preference tests. The integration of these neurobiological and behavioral datasets will determine the
significant role that circuit-specific neuroplasticity plays in the beneficial effects of extinction on motivational
and mood disturbances that contribute to cocaine addiction. A clear delineation of limbic circuits that mediate
such beneficial effects could lead to better behavioral and targeted neurostimulation approaches in the
treatm...

## Key facts

- **NIH application ID:** 9974501
- **Project number:** 5R01DA041390-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** David W Self
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $364,500
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974501

## Citation

> US National Institutes of Health, RePORTER application 9974501, Role of Extinction in Circuit-Specific Modulation of Motivation and Mood in Cocaine Addiction (5R01DA041390-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974501. Licensed CC0.

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