Search for approaches to correction of daytime sleepiness induced by dopaminergic drugs during treatment of Parkinson’s disease: Neurochemical aspects

Abstract

We proposed an approach to searching for a new drug that suppress increased daytime sleepiness induced by dopaminergic drugs during treatment of Parkinson’s disease. The search is based on the results of analysis of the effects of neuromodulators (dopamine, adenosine, and acetylcholine) on the mutually dependent functioning of the neuronal circuit motor cortex-basal ganglia-thalamus-motor cortex, which is involved in motor activity, and neural networks that regulate the sleep-wakefulness cycle and contain histaminergic cells of tuberomammillary nucleus and cells of the lateral hypothalamus, which express hypocretin/orexin and melanin- concentrating hormone (MCH). We used the unified rules of modulation of synaptic transmission, which we previously proposed. Our analysis suggests that to suppress increased daytime sleepiness it is necessary to decrease the dose of dopaminergic drugs and use drugs that contain antagonists of adenosine A1 and A2A receptors (for example, caffeine). These antagonists have an antiparkinsonian effect because they, like dopamine, can modulate corticostriatal outputs and, hencethus, facilitate motor activity. In contrast to dopaminergic drugs, they do not cause dyskinesia and cognitive disorders. Antagonists of A1 and A2A receptors also have anti-somnolent effect because they decrease MCH concentration and prevent the depressing action of endogenous adenosine on the activitiesy of cells that release orexin and histamine. Maintenance of high concentrations of orexin and histamine should promote wakefulness.