Region-Specific and Age-Dependent Multitarget Effects of Acetylcholinesterase Inhibitor Tacrine on Comprehensive Neurotransmitter Systems

ACS Chem Biol. 2022 Jan 21;17(1):147-158. doi: 10.1021/acschembio.1c00803. Epub 2021 Dec 21.

Abstract

Regional brain distribution and metabolism of neurotransmitters and their response to drug treatment are fundamentally important for understanding the central effects of neuroactive substances. We used matrix-assisted laser desorption/ionization mass spectrometry imaging in combination with multivariate analysis to visualize in anatomical detail metabolic effects of aging and tacrine-mediated acetylcholinesterase inhibition on comprehensive neurotransmitter systems in multiple mouse brain regions of 12-week-old and 14-month-old mice. We detected age-related increases in 3,4-dihydroxyphenylacetaldehyde and histamine, indicating oxidative stress and aging deficits in astrocytes. Tacrine had a significant impact on the metabolism of neurotransmitters in both age groups; predominantly, there was an increased norepinephrine turnover throughout the brain and decreased 3-methoxy tyramine, a marker for dopamine release, in the striatum. The striatal levels of histamine were only elevated after tacrine administration in the older animals. Our results demonstrated that tacrine is a multitarget and region-specific neuroactive agent, inducing age-specific responses. Although well-studied, the complete mechanisms of the action of tacrine are not fully understood, and the current findings reveal features that may help explain its treatment-related effectiveness and central side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Brain / diagnostic imaging
  • Brain Mapping*
  • Cholinesterase Inhibitors / pharmacology*
  • Dopaminergic Neurons / metabolism*
  • Least-Squares Analysis
  • Mice
  • Neurotransmitter Agents / metabolism*
  • Norepinephrine / metabolism
  • Serotonin / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Tacrine / pharmacology*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Cholinesterase Inhibitors
  • Neurotransmitter Agents
  • Serotonin
  • Tacrine
  • gamma-Aminobutyric Acid
  • Norepinephrine