# DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE

> **NIH NIH R37** · UNIVERSITY OF WASHINGTON · 2024 · $436,533

## Abstract

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. While there are many reports of opioid receptor, specifically
Kappa-opioid receptor dependent regulation of drug-seeking, there are are still few studies examining the circuit
mechanisms of stress-induced endogenous opioid peptide/receptor activity on natural reward and nicotine
reinstatement. In our first R01 cycle we determined that KORs within the basolateral amgydala, the CA1 of
hippocampus, and nucleus accumbens neurons are involved in nicotine place preference and reinstatement. In the
recent R37 cycle, we built substantially on our prior work, developing nicotine self-administration in mice so that we
can use several cutting-edge methods to assess circuit function. Here we proposed and determined that while our
lead candidate, BNST KORs were not required to reinstate nicotine seeking. We then in parallel turned to
methodically examining, other stress-sensitive, opioid peptide and receptor expressing regions including the dorsal
and ventral striatum, the BLA, the parabrachial nucleus, and the claustrum in order to determine where
dynorphin/KOR circuits are engaged to regulate, potentiate and reinstate reward seeking behaviors. Evidence from
our prior cycle, strongly suggests that amygdalar (BLA), dorsal striatum, nucleus accumbens and claustrum are
among the likely critical loci mediating the effects of opioids, including KOR on stress induced reward seeking.
However, while we isolated these regions as important for a variety of stress and reward seeking behavioral
components, the specific cell types, circuit dynamics, plasticity, and the temporal role of these circuits in reward
regulation, and nicotine IVSA is still not known. In this cycle we propose to methodically dissect how activation of
KOR, either by stress-induced endogenous opioid release, optogenetic/chemogenetic modulation of opioid peptide
release, viral CRISPR, or systemic administration of a selective opioid receptor agonists, results in altered natural
reward seeking (action-outcome) models and in reinstatement of nicotine seeking in IVSA mouse models in an
excitatory BLA to BNST circuit. We propose the following Aims: 1) determine the role of dynorphin/KOR activity in
BLA-Striatal/Accumbens circuits as necessary - sufficient for regulating stress-induced reward seeking and
reinstatement of nicotine self-administration using retrograde viral rescue (“gain of function”), in vivo pharmacology,
and conditional mouse genetics; 2) Use optogenetics and in vivo 1p/2p calcium imaging, to determine the how
dynorphin and KOR in these circuits are activated by stress and regulate reward seeking behaviors 3) Using a mouse
model of nicotine self-administration (IVSA), determine if KOR/Dynorphin in the BLA-striatal circuits are required for
stress-induced reinstatement of nicotine IVSA. These studies test our c...

## Key facts

- **NIH application ID:** 10808866
- **Project number:** 5R37DA033396-12
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Michael R. Bruchas
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $436,533
- **Award type:** 5
- **Project period:** 2013-08-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808866

## Citation

> US National Institutes of Health, RePORTER application 10808866, DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE (5R37DA033396-12). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10808866. Licensed CC0.

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