Dopamine and norepinephrine transporter inhibition for long-term fear memory enhancement

Behav Brain Res. 2020 Jan 27:378:112266. doi: 10.1016/j.bbr.2019.112266. Epub 2019 Sep 30.


Psychostimulants are highly effective cognitive-enhancing therapeutics yet have a significant potential for abuse and addiction. While psychostimulants likely exert their rewarding and addictive properties through dopamine transporter (DAT) inhibition, the mechanisms of their procognitive effects are less certain. By one prevalent view, psychostimulants exert their procognitive effects exclusively through norepinephrine transporter (NET) inhibition, however increasing evidence suggests that DAT also plays a critical role in their cognitive-enhancing properties, including long-term memory enhancement. The present experiments test the hypothesis that combined strong NET and weak DAT inhibition will mimic the fear memory-enhancing but not the addiction-related effects of psychostimulants in mice. We examined the effects of the high affinity NET inhibitors atomoxetine or nisoxetine and the low affinity DAT inhibitor bupropion, either alone or in combination, on short- and long-term memory of Pavlovian fear conditioning. We also examined the addiction-related effects of combined strong NET and weak DAT inhibition using conditioned place preference and a locomotor activity test. While atomoxetine or nisoxetine alone enhanced short-term fear memory, the addition of bupropion was required to significantly enhance long-term fear memory. Additionally, combined atomoxetine and bupropion did not produce substantial motor stimulation or place preference. These findings suggest that combining strong NET and weak DAT inhibition could lead to the development of a highly effective cognitive enhancer that lacks the potential for addiction.

Keywords: ADHD; Cognitive disorder; Context; Learning; Nootropic; Stimulant.

Publication types

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

MeSH terms

  • Animals
  • Atomoxetine Hydrochloride / administration & dosage
  • Atomoxetine Hydrochloride / pharmacology*
  • Behavior, Animal / drug effects*
  • Bupropion / administration & dosage
  • Bupropion / pharmacology*
  • Central Nervous System Stimulants / administration & dosage
  • Central Nervous System Stimulants / pharmacology*
  • Conditioning, Classical / drug effects*
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Drug Therapy, Combination
  • Fear / drug effects*
  • Female
  • Fluoxetine / administration & dosage
  • Fluoxetine / analogs & derivatives*
  • Fluoxetine / pharmacology
  • Male
  • Memory, Long-Term / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Neurotransmitter Uptake Inhibitors / administration & dosage
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Nootropic Agents / administration & dosage
  • Nootropic Agents / pharmacology*
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*


  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Neurotransmitter Uptake Inhibitors
  • Nootropic Agents
  • Norepinephrine Plasma Membrane Transport Proteins
  • Fluoxetine
  • Bupropion
  • nisoxetine
  • Atomoxetine Hydrochloride