The relatively small number of aminergic neurons located in the locus coeruleus (noradrenaline), dorsal raphe (serotonin), ventral tegmental area/substantia nigra (dopamine), lateral dorsal tegmentum/basal forebrain (acetylcholine), and tuberomamillary nucleus (histamine) project with multifold arborisations to most regions of the central nervous system, partially overlapping with the projections of hypocretin neurons.32 Apart from some distinctions they display comparable morphological features, intrinsic electrophysiological properties, and according to the reciprocal-interaction model of REM and non-REM sleep alterations, behavioral state-dependent activity patterns.21,62,63 All form mutual connections, acting in concert to control synchrony of selected cell populations throughout the entire nervous system.30,31,42,64-66 Released rarely from synaptically specialized structures (dopamine) but mostly from varicosities at some distance from their target receptors, they act by volume transmission on post- and presynaptic receptors, utilizing common or convergent signal transduction pathways19,30 to control the metabolic67 and electrical state62,63,68 of the brain.
Biogenic amines switch higher brain functions and hormonal states during hunger and satiety, during waking and sleep, during pleasure and aversion, during offense and defense, during reward and pain, during dosing and attention, during stress and contemplative life, during reproduction and cognition, during learning and memory.
3.1. Tuberomamillary Nucleus (Histamine)
Among the aminergic systems in the brain, histamine has received the least attention although it is an equally important regulator of many homeostatic body functions,21 including control of behavioral state (maintenance of wakefulness),69-71 appetite and energy metabolism, neuroendocrine regulation, nociception, and learning or memory.21 Indeed, several lines of evidence indicate an exceptionally close anatomical and functional relationship between histamine and hypocretin neurons, who exhibit mutual connectivity, cooperativity and associativity also with other neuroendocrine systems.72
The only source of neuronal histamine in the adult brain is the wake-active neurons located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus, close or adjacent to the wall of the third ventricle and perifornically close to hypocretin neurons. This puts histamine neurons in a strategic position suited to relay remote humoral-paracrine signals e.g. secreted by the ependym52,73 or circumventricular organs. Histamine neurons can be identified by their behavioral state-dependent (pacemaker-like) firing pattern and their exceptionally strong immunoreactivity to adenosine deaminase,21 a putative molecular firewall shielding wake-active histamine neurons from the somnogenic influences of adenosine.
During prolonged waking adenosine accumulates in the concourse of heightened activity in basal forebrain cholinergic arousal centers.74 Hypocretin neurons bear low affinity adenosine A1R and are sensitive (increasing c-fos immunoreactivity) to stimulant doses of the adenosine receptor antagonist caffeine, the most commonly used wake-promoting drug worldwide.7,75-77 Adenosine is also released by activation of leptomeningeal prostaglandin PGD2 receptors, localized exclusively at the ventrorostral surface of the basal forebrain, in the vicinity of sleep-active neurons in the ventrolateral preoptic area (VLPO).52 VLPO neurons release GABA and galanin, a peptide co-expressed in some histamine neurons and exerting inhibitory and neuroprotective effects.21 In contrast, PGE2 infusion into the posterior hypothalamus and TMN promotes wakefulness, increases body temperature and heart rate.52 Thus, adenosine-mediated homeostatic sleep-drive may work by A1R-mediated inhibition of wake promoting cholinergic and hypocretin but not histamine neurons, and high affinity A2R-mediated excitation of VLPO neurons. In contrast, histamine neurons in vitro16'11 and in vivo,69,70,78 strongly interact with cholinergic arousal systems70 and are controlled by constitutive histamine H3R-autoreceptors, galanin, and GABA.21
Histamine neurons express GABAA receptors with distinct subunit composition, pharmacology, and electrophysiology.17 Whole-cell recordings and single-cell RT-PCR from acutely isolated rat tuberomamillary neurons revealed differences in the expression levels of GABA receptor gamma-subunits, sensitivity to GABA and zinc, as well as in the modulation of IPSC-decay times by GABAergic drugs, such as Zolpidem, a partial benzodiazepine agonist with hypnotic but little or no amnesiac and addictive properties. Functional heterogeneity of GABAa receptors in the arousal systems may segregate the sedative and addictive effects of GABAergic drugs, including alcohol. In fact, the GABA-galaninergic pathway from sleep-active neurons in the ventrolateral preoptic area51 to the TMN16 has been identified as a (the) major and specific target for the sedative effects of GABAergic anesthetics.78
Pharmacological intervention studies in living animals, including EEG recordings in mice lacking the histamine synthesizing enzyme histidine-decarboxylase (HDC), or histamine receptors69,70 provide additional and compelling evidence, that activity of histaminergic neurons is a prerequisite for maintained wakefulness, particularly in the context of environmental challenges.69,70 HDC knockout mice exhibit normal overall sleep and wake amounts under undisturbed conditions, but wake fragmentation, increased REM sleep, slower EEG activity while awake, and an inability to maintain awake in novel environments. Similar results have been obtained from transgenic mice lacking H1 receptors.52,79 The central histamine system may thus be a key component of sustained waking and adaptive coping according to nutritional-metabolic (foraging) or noxious-immunological challenges, flight-fight stress responses, and social (resident-intruder) conflicts, which have been implicated with functions of the hypocretin system as well.11
Accumulating evidence supports a mutual positive feedback between the hypocretin and histamine system, mediated by Hcrt2- and H1-receptors, respectively. Both, the sn si effect of hypocretins on wakefulness52 as that of leptin80 or amylin81 on body weight, are blocked by H1-receptor antagonists and blunted in H1-receptor knockout mice.52 Likewise, drugs interfering with H1R functions,21 such as commonly used antihistamines or certain psychotropic drugs58 have well known sedative and/or metabolic side-effects. H1-receptor deficient mice have lower total brain hypocretin levels,82 whereas Hcrt2-receptor-deficient narcoleptic dogs have decreased histamine, but elevated dopamine/noradrenaline levels in the thalamus and cortex.82,83 Conversely, decreased dopaminergic tone in Parkinson's disease is associated with elevated histamine levels.84 This suggests that dopaminergic signaling is inversely intervened in the feedback loop between the histamine and hypocretin system.
Electrophysiological recordings from histamine and hypocretin neurons in hypothalamic slices also support the view of a positive feedback loop between the two systems. Hypocretin neurons exhibit close contact to histamine-immunoreactive fibers in hypothalamic slices.14 However, recordings from identified hypocretin neurons expressing green fluorescent protein did not reveal direct excitatory actions when exposed to histamine,26 although this does not preclude H1R-dependent long loop feed forward excitation or disinhibition through infralimbic pathways.39,85 TMN neurons (Figure 2) preferentially express Hcrt2 receptors and are densely innervated by Hcrt-containing axons forming somatic and dendritic contacts. Hypocretins, acting on postsynaptic Hcrt2 receptors depolarize histaminergic TMN neurons by activation of an electrogenic sodium-calcium exchanger (NCX) and a Ca2+ current associated with a small decrease in input resistance and increases in spontaneous firing.14 NCX in TMN neurons is also a convergent target for excitatory actions of serotonin on 5-HT2C receptors15,18 playing a role in hypocretin-induced stress-related behavioral responses (Figure 1).86 In contrast, Hcrt1 receptors in the TMN, convergent with a2-adrenoreceptor78,87 activation, increase GABA outflow from the endogenous sleep pathway of the VLPO by presynaptic mechanisms (Figure 3).16,51 Dynorphin in turn, which is highly co-expressed in hypocretin neurons and suggested to play a role in accumbens-dependent feeding responses and increased body mass index in narcolepsy,72,88 strongly suppressed. GABAergic inputs to the TMN, overwriting the facilitatory effect of hcrt-1.16
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