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.

Public Health Relevance

Cue-induced methamphetamine craving progressively increases after withdrawal from drug selfadministration. This proposal uses a rat model to investigate neural mechanisms underlying this ?incubation of methamphetamine craving? at both circuit and epigenetic levels. These studies will identify neural mechanisms underlying methamphetamine craving and relapse, and may uncover potential therapeutic targets for treating methamphetamine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Transition Award (R00)
Project #
5R00DA041350-03
Application #
9751825
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Sorensen, Roger
Project Start
2018-08-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742