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.
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.