# Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence

> **NIH NIH R21** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $74,589

## Abstract

PROJECT SUMMARY
Relapse prevention is a major goal in the treatment of alcohol use disorder (alcoholism), as many alcoholics
return to alcohol use even after a prolonged period of successful abstinence. This chronically relapsing nature
of alcoholism is thought to be exacerbated by the intensification of alcohol craving during abstinence. However,
the brain mechanism causing this intensification process remains unknown. Like alcohol craving provoked by
environmental stimuli signaling alcohol (‘alcohol cues’) in recovering alcoholics, cue-provoked alcohol seeking
in rats is known to intensify during abstinence. We have found that alcohol ‘cue-reactive’ neurons (expressing
the activation marker Fos) in the nucleus accumbens (NAc) core drive this behavioral intensification, thereby
identifying these neurons as cellular targets functionally linked to cue-provoked alcohol seeking. We also found
that these ‘cue-reactive’ neurons undergo unique transcriptional adaptations during abstinence (including those
linked to alcoholism/drug addiction) that are largely distinct from adaptations in adjacent ‘non-reactive’ neurons.
While these results provide gene targets specific to behaviorally functional neural units, we have so far
identified such adaptations (across relatively short abstinence) in rats that were well-trained to self-administer
alcohol but were not subjected to physical dependence-inducing procedures. These ‘non-dependent’ rats will
thus likely model ‘casual drinkers’ but perhaps not patients with alcoholism. Indeed, alcoholics are known to
report greater cue-provoked craving than non-dependent drinkers and show different patterns of neural cue-
reactivities. Similarly, cue-provoked alcohol seeking in rats with or without a history of physical dependence is
known to be controlled by different brain mechanisms. However, no study has yet characterized abstinence-
induced intensification of alcohol seeking in animals with dependence histories. We thus next used chronic
intermittent alcohol vapor exposures to induce physical dependence and found that alcohol dependent rats
show greater cue-provoked alcohol seeking and greater intensification of this behavior than non-dependent
rats during prolonged abstinence. These ‘dependent’ rats will thus likely better model the intensification of
alcohol craving in recovering alcoholics than ‘non-dependent’ rats, thereby providing more translational insights
into the chronically relapsing nature of alcoholism. Based on the premise above, this R21 project will test the
central hypothesis that “transcriptional adaptations unique to alcohol cue-reactive neurons in NAc core drive
the intensification of cue-provoked alcohol seeking in alcohol dependent rats undergoing prolonged
abstinence”. We will use neural activity-specific transcriptional profiling (Aim 1) and gene rescuing (Aim 2) to
selectively target alcohol ‘cue-reactive’ – rather than ‘non-reactive’ – neurons. The results will determine which
transcription...

## Key facts

- **NIH application ID:** 10686229
- **Project number:** 5R21AA030184-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PIETRO P SANNA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $74,589
- **Award type:** 5
- **Project period:** 2022-08-18 → 2024-04-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10686229

## Citation

> US National Institutes of Health, RePORTER application 10686229, Transcriptional adaptations driving the intensification of alcohol-seeking in dependent rats undergoing prolonged abstinence (5R21AA030184-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10686229. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*