Chronic paroxetine treatment prevents disruption of methamphetamine-sensitive circadian oscillator in a transgenic mouse model of Huntington's disease

Neuropharmacology. 2018 Mar 15;131:337-350. doi: 10.1016/j.neuropharm.2017.12.033. Epub 2017 Dec 21.

Abstract

Circadian abnormalities seen in Huntington's disease (HD) patients are recapitulated in several HD transgenic mouse models. In mice, alongside the master clock located in the suprachiasmatic nucleus (SCN), two other oscillators may influence circadian behaviour. These are the food-entrainable oscillator (FEO) and the methamphetamine-sensitive circadian oscillator (MASCO). SCN- and MASCO- (but not FEO-) driven rhythms are progressively disrupted in the R6/2 mouse model of HD. MASCO-driven rhythms are induced by chronic treatment with low dose of methamphetamine and characterised by an increase in period length to greater than 24 h. Interestingly, the rhythms mediated by MASCO deteriorate earlier than those mediated by the SCN in R6/2 mice. Here, we used a pharmacological strategy to investigate the mechanisms underlying MASCO-driven rhythms in WT mice. In contrast to methamphetamine, chronic cocaine was ineffective in generating a MASCO-like component of activity although it markedly increased locomotion. Furthermore, neither blocking dopamine (DA) receptors (with the DA antagonist haloperidol) nor blocking neurotransmission by inhibiting the activity of vesicular monoamine transporter (with reserpine) prevented the expression of the MASCO-driven rhythms, although both treatments downregulated locomotor activity. Interestingly, chronic treatment with paroxetine, a serotonin-specific reuptake inhibitor commonly used as antidepressant in HD, was able to restore the expression of MASCO-driven rhythms in R6/2 mice. Thus, MASCO-driven rhythms appear to be mediated by both serotoninergic and dopaminergic systems. This supports the idea that abnormalities in MASCO output may contribute to both the HD circadian and psychiatric phenotype.

Keywords: (+)-methamphetamine hydrochloride (PubChem CID: 66124); (−)-Cocaine hydrochloride (PubChem CID: 656832); haloperidol (PubChem CID: 3559); paroxetine hydrochloride hemihydrate (PubChem CID: 62878); reserpine (PubChem CID: 5770).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Circadian Clocks / drug effects*
  • Circadian Clocks / physiology
  • Circadian Rhythm / drug effects
  • Circadian Rhythm / physiology
  • Cocaine / pharmacology
  • Disease Models, Animal
  • Female
  • Huntington Disease / drug therapy*
  • Huntington Disease / physiopathology
  • Male
  • Methamphetamine / pharmacology*
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Paroxetine / pharmacology*
  • Receptors, Dopamine / metabolism
  • Serotonin / metabolism
  • Serotonin Uptake Inhibitors / pharmacology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Vesicular Monoamine Transport Proteins / antagonists & inhibitors
  • Vesicular Monoamine Transport Proteins / metabolism

Substances

  • Central Nervous System Stimulants
  • Receptors, Dopamine
  • Serotonin Uptake Inhibitors
  • Vesicular Monoamine Transport Proteins
  • Serotonin
  • Paroxetine
  • Methamphetamine
  • Cocaine