# Cellular and Circuit Mechanisms Responsible for Dynorphin Actions in mPFC

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2022 · $388,750

## Abstract

Project Summary: Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of
dysphoria and cognitive disruption. KOR activation in rodents by agonists or by stress-evoked dynorphin release
has been shown to produce aversion, increase anxiety-like behaviors, increase the rewarding effects of drugs of
abuse (e.g. cocaine, amphetamine, heroin, ethanol & nicotine), increase addictive drug self-administration, and
reinstate extinguished drug-seeking behaviors. The cellular and molecular mechanisms responsible for these
dynorphin-dependent, pro-addictive behaviors are not fully understood, and a better understanding may suggest
new therapeutic approaches to the treatment of stress-related diseases including relapse to drug use. Prior
studies supported by this award demonstrated that KOR activation in the dorsal raphe, ventral tegmentum and
ventral striatum by stress-induced release of dynorphin or pharmacological KOR agonist administration produces
aversion in mice and potentiates cocaine conditioned place preference by activating p38 MAPK in serotonergic
and dopaminergic neurons to regulate excitability and serotonin transport. Recent studies supported by this
award continued to define the molecular and cellular sites of dynorphin action in the medial prefrontal cortex
(mPFC) and mechanisms of KOR regulation of neuronal circuit function at each of these sites in brain. Studies
proposed in the present application will continue to build on this strong foundation by characterizing cellular and
molecular mechanisms responsible for dynorphin / KOR induced cognitive disruption in the mPFC. We propose
to address three questions: What are the individual contributions of pre- and postsynaptic KORs in the mPFC in
controlling behavior in an operant delayed alternation task? What are the behavioral stimuli required to evoke
dynorphin release in mPFC? What are the effects of dynorphin release and KOR activation on excitability of
mPFC neurons? Our background studies establish that pharmacological KOR activation disrupts performance
in the delayed alternation operant task, and this effect can be blocked by local KOR inactivation by a KOR
antagonist (norBNI) or by virally-mediated genetic excision of PFC KORs (AAV-Cre in the PFC of floxed KOR
male mice). The effects of KOR activation on delayed alternation performance in females are not yet known.
Stress-induced release of endogenous dynorphins in PFC also disrupt performance in the delayed alternation
task, but the efficacy of different forms of behavioral stress have not yet been established. KOR is expressed on
both pre- and postsynaptic components of the PFC circuit, but the respective contributions to controlling delayed
alternation performance are not yet understood. Preliminary results demonstrate that naloxone precipitated
withdrawal in morphine dependent male mice evokes dynorphin release in mPFC, and this suggests that
dynorphin-mediated disruption of cognition may be a compone...

## Key facts

- **NIH application ID:** 10547071
- **Project number:** 2R56DA030074-11A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Charles Chavkin
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $388,750
- **Award type:** 2
- **Project period:** 2011-03-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547071

## Citation

> US National Institutes of Health, RePORTER application 10547071, Cellular and Circuit Mechanisms Responsible for Dynorphin Actions in mPFC (2R56DA030074-11A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10547071. Licensed CC0.

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