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

Proc Natl Acad Sci U S A. 2022 Dec 13;119(50):e2208867119. doi: 10.1073/pnas.2208867119. Epub 2022 Dec 5.


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.

Keywords: compulsive drug-taking; footshock; lateral habenula; orbitofrontal cortex; substantia nigra.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Compulsive Behavior
  • Frontal Lobe / diagnostic imaging
  • Habenula* / physiology
  • Humans
  • Longitudinal Studies
  • Methamphetamine*
  • Rats
  • Substance-Related Disorders*


  • Methamphetamine