Anti-Parkinson drugs and orexin neurons

Non-ergot-type dopamine receptor agonists such as ropinirole are used for treatment of Parkinson disease, but they frequently produce adverse actions characterized by sleepiness and sleep attacks. Because these symptoms are similar to those observed in patients with narcolepsy, a sleep disorder caused by degeneration of hypothalamic orexin neurons, involvement of orexinergic system in the adverse drug actions is suspected. We found that ropinirole and other non-ergot dopamine D₂ receptor agonists cause selective loss of orexin-immunoreactive neurons in organotypic slice culture of rat hypothalamus. The mechanism of this action is considered to involve D₂ receptor-mediated presynaptic suppression of glutamatergic excitatory inputs to orexin neurons because continuous silencing of excitatory activity of orexin neurons can deplete orexin from cell bodies. In addition, Parkinson disease itself may accompany loss of orexin neurons. Disturbance of orexinergic system may play an important role in sleep/arousal dysfunctions under these and other clinical conditions.