Nicotinic receptor modulation of the default mode network

Psychopharmacology (Berl). 2021 Feb;238(2):589-597. doi: 10.1007/s00213-020-05711-9. Epub 2020 Nov 20.

Abstract

Rationale: Previous neuroimaging studies of cognition involving nicotinic acetylcholine receptor (nAChR) agonist administration have repeatedly found enhanced task-induced deactivation of regions of the default mode network (DMN), a group of brain systems that is more active at rest and mediates task-independent thought processes. This effect may be related to pro-cognitive nAChR agonist effects OBJECTIVES: The present study sought to test whether nAChR modulation of the DMN is bi-directional, i.e., whether a nAChR antagonist would reduce task-induced deactivation.

Methods: Eighteen healthy non-smokers underwent functional magnetic resonance imaging while performing a letter N-back task. Scans were performed after nicotine administration (7 mg/24 h, transdermally), after administration of the nAChR antagonist mecamylamine (7.5 mg, p.o.), and after double placebo, in counterbalanced sequence. Blood-oxygen-level-dependent (BOLD) signal was analyzed within ventromedial prefrontal cortex (vmPFC) and posterior cingulate cortex (PCC) regions of interest-central hubs of the DMN in which consistent nAChR agonist-induced changes had previously been identified.

Results: Nicotine enhanced hit rate in both the 0-back and 2-back condition, while mecamylamine slowed reaction time in the 2-back condition. Mecamylamine reduced task-induced deactivation of vmPFC and PCC. Nicotine had no significant effects on the BOLD signal.

Conclusions: The finding that nAChR tone reduction by mecamylamine weakened task-induced DMN deactivation indicates that a constant tone of nAChR activation helps regulate DMN activity in healthy individuals. This suggests that low nAChR tone may play a causal role in DMN dysregulation seen in conditions such as mild cognitive impairment or Alzheimer's disease.

Keywords: Cognition; Deactivation; Default mode network; Mecamylamine; N-back; Nicotine; Nicotinic acetylcholine receptor; fMRI.

MeSH terms

  • Adult
  • Brain / diagnostic imaging
  • Brain / drug effects*
  • Brain / metabolism
  • Cognition / drug effects*
  • Cognitive Dysfunction / metabolism
  • Default Mode Network / diagnostic imaging
  • Default Mode Network / drug effects*
  • Default Mode Network / metabolism
  • Female
  • Gyrus Cinguli / drug effects
  • Gyrus Cinguli / metabolism
  • Humans
  • Magnetic Resonance Imaging*
  • Male
  • Mecamylamine / pharmacology
  • Middle Aged
  • Nicotine / pharmacology
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / pharmacology*
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Reaction Time / drug effects
  • Receptors, Nicotinic / metabolism*
  • Task Performance and Analysis

Substances

  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • Mecamylamine
  • Nicotine