EDS in Parkinson’s disease: pharmacology and new mouse model

Abstract

Excessive daytime sleepiness (EDS) can affect 20–50% of patients with Parkinson’s disease (PD), and sudden onset of sleep attacks (SA) in PD behind the wheel often leads to fatal car accidents. Although non-treated PD patients exhibit EDS and SA, SA in PD is often associated with use of DA agonists, especially the recent non-ergot DA D2/3 agonists. We have therefore initiated a pharmacological study to study the pharmacodynamics of the D2/3 agonists on sleep. Male rats underwent surgery for EEG and EMG electrodes. Vehicle was injected (i.p.) 5 min before the beginning of lights-off period (ZT12) on day 1, and sleep was recorded for 24-h. On day 2, quinpirole (Qu: 30 μ g or 1000 μ g/kg), a non-ergot DA D2/3 agonist, was injected. Amounts of sleep parameters for the 24-h following Qu administration were compared to those following vehicle injections. Change in the extracellular DA levels after drug administration was also measured in the prefrontal cortex. Low dose of Qu significantly increased SWS and REM sleep, and decreased wakefulness. On the contrary, high dose of Qu significantly enhanced wakefulness which lasted for 3–4 h followed by a large increase in sleep that lasted until the end of the active period. This increase in sleep was much larger than the sleep loss in the initial hours, and was also much larger than sleep rebound seen after the total sleep deprivation of 4-h (ZT12-16). A low dose of Qu reduced DA release immediately by 60%, and the level gradually returned to the baseline over 7-h. A high dose of Qu produced much longer reduction in DA release, and the effect lasted for 12-h. Interestingly, the recovery of DA release started to occur at 4 h after the high dose injection, and the slope of the recovery after 4 h is identical to the slope that occurred after the low quinpirole dose administration (which accompanied sleep induction). D2/3 agonists reduce dopamine release by acting on pre-synaptic D2/3 autoreceptors, while high doses predominantly activate postsynaptic D2 receptors. The results of microdialysis experiments suggest that a shift from postsynaptic (excitatory) to presynaptic (inhibitory) action may occur 4 h after the administration of a high dose of Qu. This mechanism may partially explain the D2/D3 agonist-induced excessive sleepiness seen in human patients and we are testing this hypothesis using a new mouse model of PD with cre-loxP recombinant conditional knockout of DA neurons. Research supported by R21 NS072942.