Treatment with the MAO-A inhibitor clorgyline elevates monoamine neurotransmitter levels and improves affective phenotypes in a mouse model of Huntington disease

Exp Neurol. 2016 Apr;278:4-10. doi: 10.1016/j.expneurol.2016.01.019. Epub 2016 Jan 26.

Abstract

Abnormal monoamine oxidase A and B (MAO-A/B) activity and an imbalance in monoamine neurotransmitters have been suggested to underlie the pathobiology of depression, a major psychiatric symptom observed in patients with neurodegenerative diseases, such as Huntington disease (HD). Increased MAO-A/B activity has been observed in brain tissue from patients with HD and in human and rodent HD neural cells. Using the YAC128 mouse model of HD, we studied the effect of an irreversible MAO-A inhibitor, clorgyline, on the levels of select monoamine neurotransmitters associated with affective function. We observed a decrease in striatal levels of the MAO-A/B substrates, dopamine and norepinephrine, in YAC128 HD mice compared with wild-type mice, which was accompanied by increased anxiety- and depressive-like behaviour at five months of age. Treatment for 26 days with clorgyline restored dopamine, serotonin, and norepinephrine neurotransmitter levels in the striatum and reduced anxiety- and depressive-like behaviour in YAC128 HD mice. This study supports a potential therapeutic use for MAO-A inhibitors in the treatment of depression and anxiety in patients with HD.

Keywords: Anxiety; Depression; Huntington's disease; Monoamine oxidase; Monoamine oxidase inhibitors; Monoamines; Mouse model; Psychiatric features.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Clorgyline / therapeutic use*
  • Disease Models, Animal*
  • Exploratory Behavior / drug effects
  • Hindlimb Suspension
  • Humans
  • Huntingtin Protein
  • Huntington Disease / complications*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Transgenic
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / therapeutic use*
  • Mood Disorders* / drug therapy
  • Mood Disorders* / etiology
  • Mood Disorders* / metabolism
  • Mutation / genetics
  • Nerve Tissue Proteins / genetics
  • Neurotransmitter Agents / metabolism*
  • Phenotype
  • Swimming

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Monoamine Oxidase Inhibitors
  • Nerve Tissue Proteins
  • Neurotransmitter Agents
  • Monoamine Oxidase
  • Clorgyline