The role of tuberomammillary nucleus histaminergic neurons, and of their receptors, in the regulation of sleep and waking

Abstract

Summary Neuroanatomical, neurochemical, genetic, and neuropharmacological evidence presently indicates a role for histamine (HA) in the control of behavioral states. The known neuroanatomical connections of the HA-ergic pathways resemble those of the ascending noradrenergic and serotonergic components of the reticular activating system. Also, the arousing effect of intracerebroventricular (icv) HA administration indicates an important role for HA in this system as a major determinant of the waking state. This is further supported by findings in which 2-(3-trifluoromethylphenyl)histamine, the selective H1 receptor agonist, and thioperamide, the H3 receptor antagonist, increase waking while the HA synthesis inhibitor α-FMH, the H1 receptor antagonists mepyramine, diphenhydramine, chlorpheniramine, and promethazine, and the H3 receptor agonist AMH produce the opposite effects. It has been proposed that HA may act to modulate REM sleep, such that inhibition of HA functional activity would be followed by increased amounts of REM sleep (permissive role). Accordingly, during REM sleep HA-containing neurons become silent. Moreover, rats treated with α-FMH and HD-KO mice show a significant increase of REM sleep. However, stimulation or blockade of the H1 or H3 receptor suppresses REM sleep. These seemingly conflicting sets of data could be partly related to the lack of specificity of drugs that modify HA transmission. However, experimental manipulations involving direct interactions with receptors may not necessarily have the same consequences for REM sleep as would manipulations that result in reduced HA availability. In this respect, the suppression of REM sleep after stimulation of H1 receptors could be related to the activation of GABAergic interneurons located within and around the LDT/PPT that express these receptors. On the other hand, the reduction of REM sleep after activation of H3 heteroreceptors located in cholinergic and glutamatergic neurons of the LDT/PPT and the mPRF involved in the induction and maintenance of REM sleep could be related to the inhibition of the release of ACh and GLU.