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Pathogenic mechanisms
B28 Neural mechanisms underlying the dysfunction of the methamphetamine-sensitive circadian oscillator (MASCO) in a mouse model of Huntington's disease
  1. K Ouk,
  2. JH Aungier,
  3. M Cuesta,
  4. AJ Morton
  1. University of Cambridge, Cambridge, UK

Abstract

Background A progressive disintegration of the rest-activity rhythm is seen in the R6/2 mouse model of Huntington's disease. Circadian rhythms are orchestrated by the master clock located within the suprachiasmatic nucleus, but rest-activity rhythms can also be regulated by extra-suprachiasmatic nucleus oscillators such as the methamphetamine-sensitive circadian oscillator (MASCO). The MASCO is activated by placing WT mice under constant darkness and treating them chronically with methamphetamine (MAP). MAP alters the circadian rhythm measured via locomotor activity by significantly increasing the period. The MASCO is dysfunctional in presymptomatic R6/2 mice but can be partially restored by L-DOPA replacement therapy. This suggests a presymptomatic abnormality of the catecholaminergic systems in R6/2 mice.

Aims Our aim was to investigate the neuronal mechanism underlying the MASCO and to understand the contribution that a deficient MASCO makes to the progressive disintegration of the rest-activity rhythm observed in R6/2 mice.

Methods WT mice were placed under constant darkness. The rest-activity rhythm was measured continuously using passive infrared movement sensors. Mice were given a chronic low dose of MAP (0.005%) via the drinking water to induce the MASCO. Some groups were also treated chronically with the D2 receptor antagonist haloperidol (0.01 or 0.05 mg/kg/day), reserpine (1 mg/kg/day) or cocaine (20 or 30 mg/kg/day).

Results Haloperidol did not block the MASCO, suggesting that D2 receptors are not an essential mediator of this oscillator. Depletion of catecholamines using chronic reserpine treatment also did not fully block the MASCO in WT mice. Finally, cocaine given chronically did not induce MASCO-like changes in activity.

Conclusion Together these results suggest that dopamine neurotransmission alone does not underlie the generation of the MASCO. More specific drugs or lesion studies need to be tested before we can understand the mechanisms.

  • Rest-activity rhythm
  • behaviour
  • R6/2

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