A mouse model of sleep disorders in Parkinson’s disease showing distinct effects of dopamine D2-like receptor activation

Abstract

Excessive daytime sleepiness (EDS) and sleep fragmentation are often observed in Parkinson’s disease (PD) patients and are poorly understood despite their considerable impact on quality of life. We examined the ability of a neurotoxin-based mouse model of PD to reproduce these disorders and tested the potential counteracting effects of dopamine replacement therapy. Experiments were conducted in female mice with a unilateral 6-hydroxydopamine lesion of the medial forebrain bundle, leading to the loss of dopamine neurons projecting to the dorsal and ventral striatum. Sham-operated mice were used as control. Electroencephalographic and electromyographic recording was used to identify and quantify awaken, rapid eye movement (REM) and non-REM (NREM) sleep states. PD mice displayed enhanced NREM sleep and reduced wakefulness during the active period of the 24-hour circadian cycle, indicative of EDS. In addition, they also showed fragmentation of NREM sleep and increased slow-wave activity, a marker of sleep pressure. Electroencephalographic analysis of the PD model also revealed decreased density and increased length of burst-like thalamocortical oscillations (spindles). Treatment of PD mice with the dopamine receptor agonist, pramipexole, but not with L-DOPA, counteracted EDS by reducing the number, but not the length, of NREM sleep episodes during the first half of the active period. The present model recapitulates some prominent PD-related anomalies affecting sleep macro- and micro-structure. Based on the pharmacological profile of pramipexole these results also indicate the involvement of impaired dopamine D2/D3 receptor transmission in EDS.