# Cellular and circuit adaptations contributing to the incubation of oxycodone craving

> **NIH NIH R16** · NORTH CENTRAL COLLEGE · 2024 · $159,201

## Abstract

PROJECT SUMMARY
Recently, opioid use and dependence has increased to epidemic levels. A prominent contributor to this trend is
oxycodone, (Oxy), a semisynthetic opioid analgesic and most widely-prescribed opioid painkiller. A major hurdle
in addiction treatment, including for opioid addicts, is a long-lasting vulnerability to relapse. Evidence indicates
that the drugs of abuse produce long-lasting maladaptive plasticity in nucleus accumbens (NAc) synaptic function
that underlie compulsive drug seeking. Such plasticity accounts for the fact that cue-induced craving
progressively intensifies (‘incubates’) over weeks/months of forced abstinence or withdrawal in both humans and
animals, for many drug classes. During withdrawal from extended-access Oxy self-administration, rats exhibit a
progressive intensification (incubation) of cue-induced Oxy craving that is accompanied by adaptations in in
AMPA receptor subunit composition in the NAc, similar to other drugs. A key challenge is how to reverse this
plasticity in a translationally-relevant manner. Growing evidence suggests that subanesthetic doses of the
glutamate-NMDA receptor antagonist ketamine (Ket) may be a potential long-lasting treatment option for
substance use disorders. Our preliminary data show systemic subanesthetic Ket, given daily during withdrawal
from Oxy self-administration in rats, reduces incubation in a seeking test one day after the last Ket injection.
There are 3 objectives of this proposal: (1) characterize the time course of Ket’s ability to reduce Oxy incubation,
(2) determine an effective dosing regimen and timepoint for therapeutic intervention, and (3) test potential
mechanisms for Ket’s effect. The central hypothesis is that altered activity and/or altered protein translation in
the reward circuitry is responsible for Oxy incubation and that Ket may be exerting its effects by normalizing
pathological changes. Aim 1 will determine the duration of incubation reduction by repeated Ket and test
a role for projection-specific changes in glutamate afferents to the NAc. cFos (an indirect marker of neural
activity) immunohistochemistry will be combined with retro-AAV viral tracing to examine input-specific activity in
key regions of the reward circuitry that project to the NAc: orbitofrontal cortex, basolateral amygdala, and ventral
subiculum of the hippocampus. Activity will be assessed at 4 points after discontinuing Oxy self-administration:
withdrawal day 1 (WD1), before adaptations have occurred, WD15, when craving has “incubated”, or at WD30
or WD45, to assess the persistence of incubation. The effects of daily subanesthetic Ket will also be examined
to determine the duration of its effects. Aim 2 will characterize protein synthesis during Oxy incubation.
Puromycin labeling will be used to measure protein translation of the key AMPA receptor subunits GluA1 and
GluA2 in NAc tissue on WD1 and WD15. Daily Ket’s impact on AMPAR translation will also be examined. Aim
3 will exam...

## Key facts

- **NIH application ID:** 10936968
- **Project number:** 1R16DA062584-01
- **Recipient organization:** NORTH CENTRAL COLLEGE
- **Principal Investigator:** Michael Thomas Stefanik
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $159,201
- **Award type:** 1
- **Project period:** 2024-08-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936968

## Citation

> US National Institutes of Health, RePORTER application 10936968, Cellular and circuit adaptations contributing to the incubation of oxycodone craving (1R16DA062584-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10936968. Licensed CC0.

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