Sleep as neuronal detoxification and restitution.

The classical 'hypnotoxin theory' was followed by extensive search for an endogenous sleep substance. Brain tissues and body fluids of sleeping and sleep-deprived animals contained active sleep-inducing factors like the sleep-promoting substance (SPS). Uridine and oxidized glutathione (GSSG), two components of SPS, seem to regulate physiological sleep differentially. Uridine may facilitate the inhibitory neurotransmission at the synaptic level of the GABAA-uridine receptor complex. In contrast, GSSG may inhibit the excitatory neurotransmission at the synaptic level of the glutamate receptor. Thus, the two SPS components promote sleep by exerting a complementary action on the two major neurotransmitter systems in the brain that have mutually reciprocal functions. Further, among multidimensional functions of sleep, uridine may contribute to recover the activity of neurons, while glutathione may counteract excitotoxic events. Hence sleep at the behavioral level is a process of neuronal restitution and detoxification at the cellular level. Such a concept can be regarded as a modern version of the Ishimori-Piéron's hypnotoxin theory proposed early in this century.