Citation

Hu Y, Salmeron BJ, Krasnova IN, Gu H, Lu H, Bonci A, Cadet JL, Stein EA, Yang Y. Proc. Natl. Acad. Sci. U. S. A. 2019; 116(18): 9066-9071.

Affiliation

Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Programs, National Institutes of Health, Baltimore, MD 21224; yihongyang@intra.nida.nih.gov huyuzheng@zju.edu.cn.

Copyright

(Copyright © 2019, National Academy of Sciences)

DOI

10.1073/pnas.1819978116

PMID

30988198

Abstract

Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal "go" circuit and a decreased prelimbic cortex-ventrolateral striatal "stop" circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, "shock-resistant" rats showed strengthening of this negative connectivity after shock exposure. In contrast, "shock-sensitive" rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs.

Language: en

Keywords

compulsive behavior; foot shock punishment; frontostriatal functional circuits; functional connectivity; methamphetamine self-administration