Compulsive drug-taking is associated with habenula-frontal cortex connectivity

Study Authors Ying Duan and Pei-Jung Tsai

Featured Paper of the Month – March 2023

Published in PNAS by Ying Duan, Pei-Jung Tsai and Yihong Yang, et al. from the NIDA IRP Magnetic Resonance Imaging and Spectroscopy Section.

Summary

Compulsive drug use, as the defining feature of substance use disorder, is attributed to disadvantageous decision-making and has been associated with dysfunction of frontal-midbrain systems. The habenula is a relay node between forebrain and midbrain regions and processes negative feedback in response to aversive events. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, we collected functional MRI data at pretraining baseline, after 20 days of long-access self-administration phase, and after 5 days of concomitant footshock coupled with self-administration (punishment phase). Individual differences in response to punishment were quantified by a compulsivity index, defined as drug infusions at the end of punishment phase, normalized by those at the end of self-administration phase. We found that after the punishment phase, functional connectivity of habenula-frontal cortex and habenula-substantia nigra circuits was positively correlated with the compulsivity index in shock-resistant rats that continued to take drug during the concurrent footshock. In contrast, functional connectivity of the same circuits was negatively correlated with the compulsivity index in shock-sensitive rats that significantly reduced drug-taking during the punishment phase. These findings suggest that frontal-habenula-midbrain circuits may distinctly regulate reward/punishment processing in shock-resistant versus shock-sensitive rats, and these circuits may serve as therapeutic targets for individualized treatment of substance use disorders.

Publication Information

Duan, Ying; Tsai, Pei-Jung; Salmeron, Betty Jo; Hu, Yuzheng; Gu, Hong; Lu, Hanbing; Cadet, Jean Lud; Stein, Elliot A; Yang, Yihong

Compulsive drug-taking is associated with habenula-frontal cortex connectivity Journal Article

In: Proc Natl Acad Sci U S A, vol. 119, no. 50, pp. e2208867119, 2022, ISSN: 1091-6490.

Abstract | Links

@article{pmid36469769b,

title = {Compulsive drug-taking is associated with habenula-frontal cortex connectivity},

author = {Ying Duan and Pei-Jung Tsai and Betty Jo Salmeron and Yuzheng Hu and Hong Gu and Hanbing Lu and Jean Lud Cadet and Elliot A Stein and Yihong Yang},

url = {https://pubmed.ncbi.nlm.nih.gov/36469769/},

doi = {10.1073/pnas.2208867119},

issn = {1091-6490},

year  = {2022},

date = {2022-12-01},

urldate = {2022-12-01},

journal = {Proc Natl Acad Sci U S A},

volume = {119},

number = {50},

pages = {e2208867119},

abstract = {As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a "compulsivity index (CI)," defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.},

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pubstate = {published},

tppubtype = {article}

}