# DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE

> **NIH NIH R37** · UNIVERSITY OF WASHINGTON · 2020 · $415,113

## Abstract

Activation of kappa opioid receptors (KOR) in humans elicits dysphoria, and KOR activation by agonists or by
stress-induced dynorphin release in rodents produces reinstatement of drug seeking. Despite recent efforts to
curb use, nicotine use is at an all time high, is responsible for millions of deaths each year and remains one of
the most difficult drugs to stop using. The aversive effects of dynorphin/KOR system activity have been linked
to increased drug self-administration, and this system is known to cause reinstatement of drug seeking (heroin,
cocaine, alcohol). While many reports of KOR dependent regulation of drug-seeking exist, there are are still
few studies examining the role and mechanisms of stress-induced dynorphin-KOR activity on nicotine
reinstatement. In our prior R01 grant cycle we sought to determine whether stress-induced reinstatement of
nicotine preference is mediated through dynorphin and KOR, and mapped the critical brain regions where
nicotine preference, and KOR and dynorphin mediated nicotine reinstatement occur. We determined that the
amgydala, CA1 of hippocampus, and nucleus accumbens neurons are involved in nicotine place preference
and reinstatement. We also established a reinstatement model of nicotine self-administration in mice that is
KOR dependent. However, the neural networks, dynamics and circuit mechanisms responsible for KOR-dependent nicotine reinstatement are not understood. Understanding how dynorphinergic neural circuits and
KOR cause nicotine reinstatement provides valuable and important insights and new therapeutic approaches
to the treatment and prevention of stress-related nicotine relapse. Evidence from our prior cycle strongly
suggests that amygdalar (BLA) and extended amgydala (BNST) circuits are the critical loci mediating the
effects of KOR on reinstatement. However, while we isolated this region as important, the specific cell types,
circuit dynamics, plasticity, and the temporal role of circuit in nicotine reinstatement is not known. In this cycle
we propose to methodically dissect how activation of KOR, either by stress-induced dynorphin release,
optogenetic/chemogenetic modulation of dynorphin release, or systemic administration of a selective KOR
agonist, results in reinstatement of nicotine place preference in an excitatory BLA to BNST circuit. We propose
the following Aims using an array of approaches: 1) determine the role of dynorphin/KOR activity in a BLA to
BNST circuit as necessary and sufficient for stress-induced reinstatement of nicotine preference using
retrograde viral rescue (“gain of function”), in vivo pharmacology, and conditional mouse genetics; 2) Use
optogenetics and in vivo calcium imaging to determine the how dynorphin and KOR+ BLA to BNST circuits are
activated by stress, and during reinstatement; 3) Using a mouse model of nicotine self-administration (IVSA),
determine if KOR/Dynorphin in the BLA-BNST circuit is required for stress-induced reinstatement of nicotine
IV...

## Key facts

- **NIH application ID:** 9893834
- **Project number:** 5R37DA033396-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Michael R. Bruchas
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $415,113
- **Award type:** 5
- **Project period:** 2013-08-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893834

## Citation

> US National Institutes of Health, RePORTER application 9893834, DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE (5R37DA033396-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893834. Licensed CC0.

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