Mechanisms involved in the inhibition of REM sleep by serotonin

Abstract

Based on electrophysiological, neurochemical, and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions to promote waking (W) and to inhibit (permissive role) REM sleep (REMS). Serotonergic neurons of the dorsal raphe nucleus (DRN) fire at a steady rate during W, decrease their firing during slow-wave sleep (SWS), and virtually cease activity during REMS. Serotonin released during W activates 5-HT1A somatodendritic receptors and 5-HT2A/2C receptors expressed by GABAergic interneurons, and induces a decrease of the firing rate of 5-HT cells characteristic of SWS. In addition to local inhibitory circuits, GABAergic neurons of the ventrolateral preoptic nucleus play a role in the deactivation of the 5-HT and all other arousal systems, which results in the occurrence of REMS. Studies on the effects on REMS of direct administration of selective 5-HT1A (8-OH-DPAT, flesinoxan), and 5-HT2A/2C (DOI) receptor agonists into the DRN tend to indicate that quite different mechanisms are involved in their effects. Direct infusion of 8-OH-DPAT or flesinoxan into the DRN significantly enhances REMS, and this effect is prevented by local infusion of the selective 5-HT1A receptor antagonist WAY 100635. In agreement with the reciprocal interaction hypothesis of REMS generation, inhibition of DRN serotonergic neurons following somatodendritic 5-HT1A receptor stimulation suppressed 5-HT inhibition of mesopontine cholinergic neurons and increased REMS. Infusion of DOI into the DRN induces a significant reduction of REMS in the rat. Pretreatment with selective 5-HT2A and 5-HT2C receptor antagonists prevents the DOIinduced suppression of REMS. Serotonin-containing neurons of the DRN do not express 5-HT2A or 5-HT2C receptors. The 5-HT2A and 5-HT2C receptor-containing neurons are predominantly GABAergic interneurons and projection neurons. Since DOI inhibits the firing of serotonergic neurons in the DRN and reduces the extracellular concentration of 5-HT, it can be proposed that the DOI activation of long-projection GABAergic neurons that express 5-HT2A/2C receptors would be responsible for the inhibition of cholinergic cells in the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT/PPT) and the suppression of REMS. Microinjection of 8-OH-DPAT or flesinoxan into the LDT/PPT induces an inhibitory response on target neurons and the suppression of REMS. Moreover, infusion of DOI into the LDT/PPT selectively decreases REMS. In this respect, activation of 5-HT2A/2C receptors expressed by GABAergic interneurons in the LDT/PPT would produce the local release of GABA and the reduction of the behavioral state.