Interactions between GABAergic and serotonergic processes in the dorsal raphe nucleus in the control of REM sleep and wakefulness

Abstract

Based on electrophysiological, neurochemical, genetic, and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions to promote wakefulness (W) and to inhibit rapid-eye-movement sleep (REMS). The dorsal raphe nucleus (DRN) has been subdivided into several clusters on the basis of differences in cellular morphology, expression of other neurotransmitters, and afferent and efferent connections. These differences among subpopulations of 5-HT neurons may have important implications for neural mechanisms underlying 5-HT modulation of sleep and wakefulness. The DRN contains 5-HT and non5-HT neurons. The latter express a variety of substances including γ-aminobutyric acid (GABA). The serotonergic cells are present throughout the rostral-caudal extent of the DRN, in all subdivisions of the nucleus. However, they predominate along the midline of the rostral, ventral, and dorsal subdivisions of the raphe nucleus and fire broad spikes with low frequency and a high regular pattern. The activity of DRN serotonergic neurons is greatest during W; it diminishes during slow-wave sleep and is virtually suppressed when the animal starts REMS. GABAergic neurons are abundant throughout the DRN. Although most of the DRN subdivisions contain GABAergic interneurons, they predominate in the lateral wings of the raphe nucleus. All these neurons have significantly faster rates and narrower spike widths than the 5-HT-containing cells. Local microinjection of 5-HT1B, 5-HT2A/2C, and 5-HT7 receptor agonists into the DRN selectively suppresses REMS in the rat. On the other hand, local administration of the GABAA receptor agonist muscimol into the neuroanatomical structure increases REMS in laboratory animals. The inhibition of GABAergic interneurons that express 5-HT1B receptor and the activation of long-projection GABAergic interneurons that express 5-HT2A/2C or 5-HT7 receptors could be tentatively responsible for the inhibition of cholinergic cells of the laterodorsal and pedunculopontine tegmental nuclei and the suppression of REMS. In contrast, the direct inhibition of DRN 5-HT neurons by muscimol tends to facilitate the occurrence of REMS. It has been established that inhibitory and facilitatory neurotransmitter systems project to the DRN and regulate the activity of 5-HT neurons during the sleep-wake cycle. Among the former is the GABAergic system that can promote REMS by deactivating 5-HT neurons. The finding that direct microinjection of 5-HT1B, 5-HT2A/2C, and 5-HT7 receptor ligands into the DRN interferes with the occurrence of REMS points to the existence of a supplemental mechanism in the control of 5-HT neurons functional activity.