# Circuit and epigenetic mechanisms underlying incubation of methamphetamine craving

> **NIH NIH R00** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $249,000

## Abstract

Cue-induced drug craving progressively increases after withdrawal, a phenomenon termed ‘incubation of
drug craving’. During the last decade, mechanistic studies have primarily focused on incubation of cocaine
craving. In contrast, very few studies have examined the mechanisms underlying incubation of
methamphetamine (Meth) craving. Here, I propose to study circuit and epigenetic mechanisms underlying
incubation of Meth craving with a focus on the dorsal striatum (DS) region. The choice of this brain area is based
on my preliminary data implicating a critical role of DS neuronal activity and a potential role of DS histone
deacetylase 5 (HDAC5, an epigenetic-related enzyme) in incubation of Meth craving. At the circuit level, I will
use a retrograde tracing technique (CTb, cholera toxin subunit B) in combination with the neuronal activity
marker Fos to identify critical afferent projections to the DS that are activated during incubation of Meth craving.
Next, I will use a novel retro-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) method to
study the causal role of afferent projections to the DS in incubation of Meth craving. At the epigenetic level, I will
combine chromatin immunoprecipitation-sequencing (ChIP-seq) with RNA-sequencing (RNA-seq) to identify
downstream gene targets of HDAC5 in DS whose expression is altered after prolonged withdrawal (1 month)
from Meth self-administration. I will also use the CRISPR-Cas9 system to examine the causal role of DS HDAC5
in incubation of Meth craving. My proposal will provide new insights on the mechanisms underlying Meth craving
and relapse. Additionally, under the mentorship of Drs. Shaham, Nestler, and Cowan the proposal will provide
me with an ideal training environment to prepare me for a future independent career as a researcher in an
academic setting who explores basic mechanisms of drug addiction.

## Key facts

- **NIH application ID:** 9983619
- **Project number:** 5R00DA041350-04
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Xuan Anna Li
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983619

## Citation

> US National Institutes of Health, RePORTER application 9983619, Circuit and epigenetic mechanisms underlying incubation of methamphetamine craving (5R00DA041350-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9983619. Licensed CC0.

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