Increased habenular connectivity in opioid users is associated with an α5 subunit nicotinic receptor genetic variant

Am J Addict. 2017 Oct;26(7):751-759. doi: 10.1111/ajad.12607. Epub 2017 Aug 31.


Background and objectives: Opioid use disorder (OUD) is a chronic disorder with relapse based on both desire for reinforcement (craving) and avoidance of withdrawal. The aversive aspect of dependence and relapse has been associated with a small brain structure called the habenula, which expresses large numbers of both opioid and nicotinic receptors. Additionally, opioid withdrawal symptoms can be induced in opioid-treated rodents by blocking not only opioid, but also nicotinic receptors. This receptor co-localization and cross-induction of withdrawal therefore might lead to genetic variation in the nicotinic receptor influencing development of human opioid dependence through its impact on the aversive components of opioid dependence.

Methods: We studied habenular resting state functional connectivity with related brain structures, specifically the striatum. We compared abstinent psychiatric patients who use opioids (N = 51) to psychiatric patients who do not (N = 254) to identify an endophenotype of opioid use that focused on withdrawal avoidance and aversion rather than the more commonly examined craving aspects of relapse.

Results: We found that habenula-striatal connectivity was stronger in opioid-using patients. Increased habenula-striatum connectivity was observed in opioid-using patients with the low risk rs16969968 GG genotype, but not in patients carrying the high risk AG or AA genotypes.

Conclusions: We propose that increased habenula-striatum functional connectivity may be modulated by the nicotinic receptor variant rs16969968 and may lead to increased opioid use.

Scientific significance: Our data uncovered a promising brain target for development of novel anti-addiction therapies and may help the development of personalized therapies against opioid abuse. (Am J Addict 2017;26:751-759).

MeSH terms

  • Adult
  • Avoidance Learning / physiology
  • Connectome / methods*
  • Corpus Striatum
  • Female
  • Genetic Predisposition to Disease
  • Habenula* / metabolism
  • Habenula* / physiopathology
  • Humans
  • Magnetic Resonance Imaging / methods
  • Male
  • Nerve Tissue Proteins / genetics*
  • Opioid-Related Disorders* / diagnosis
  • Opioid-Related Disorders* / genetics
  • Opioid-Related Disorders* / metabolism
  • Opioid-Related Disorders* / psychology
  • Receptors, Nicotinic / genetics*
  • Substance Withdrawal Syndrome* / diagnosis
  • Substance Withdrawal Syndrome* / metabolism
  • Substance Withdrawal Syndrome* / psychology


  • CHRNA5 protein, human
  • Nerve Tissue Proteins
  • Receptors, Nicotinic
  • nicotinic receptor alpha5 subunit, human