CREB-phosphorylation is increased via the 5-HT(1A)-receptor: Reason for the modulatory effects of SSRI on sleep/wake regulation?

The cyclic AMP-response element binding protein (CREB) is an activity-dependent transcription factor important for synaptic plasticity and memory storage. Levels of phosphorylated CREB within the cortex are higher in waking than in sleep, suggesting that CREB plays also a role in sleep/wake regulation in mammals. We have tested SSRI for their ability to modulate CREB-phosphorylation since they are known to decrease total sleeptime, and the amount of REM-sleep and increase periods of wakefulness following sleep onset in humans. For in vitro testing we used Jurkat cells. According to the acute effects of SSRI on sleep regulation they also increased CREB-phosphorylation within one hour in vitro. We tested the monocyclics alaproclate (a reversible non competitive NMDA antagonist and a specific inhibitor of serotonine reuptake) and fluoxetine, the bicyclic nitroquipazine (a selective serotonine reuptake inhibitor) and the tricyclic imipramine. All these substances equally induced CREB-phosphorylation. This effect was inhibited by the 5-HT(1A) antagonist WAY 100635 but not the 5-HT(2A) antagonist ketanserin. This suggests that SSRIs increase CREB-phosphorylation via the 5-HT(1A)-receptor. This might be the essential signal transduction pathway that mediates the effects of SSRI on sleep/wake regulation. This presumption is confirmed by the finding, that the 5-HT(1A) agonist and anxiolytic buspirone shows no sedative effects.