Contribution of Histamine Type-1 Receptor to Metabolic and Behavioral Control of Ventilation

Abstract

Histaminergic neurons in the hypothalamus are well documented as being involved in the control of autonomic functions, such as the balance of energy metabolism and circadian rhythm. We tested the hypothesis that an activation of the histamine type-1 (H1) receptor is required for the control of ventilation during the course of a day in free-moving mice. Ventilation, aerobic metabolism, and electroencephalogram were measured by a whole-body-plethysmograph, a magnetic-type mass spectrometry system, and a telemetry system, respectively, in H1 receptor-knockout (H1RKO) and wild-type mice. Both genotypes showed daily oscillations in minute ventilation ( E ) and oxygen consumption ( o 2 ), with greater values during the dark period compared to the light period. In the latter, H1RKO mice showed increased E and CO 2 excretion ( co 2 ) relative to wild-type mice, and E was comparable to the co 2 increase. However, there was no change in o 2 in H1RKO mice, suggesting that differences in co 2 between genotypes are responsible for differences in E during the light period. During the dark period, co 2 was elevated in H1RKO mice compared with WT mice. Because there was no difference in E , the ratio of E to co 2 was reduced in H1RKO mice. Electroencephalogram results suggested that this might be due to a depressed arousal state in H1RKO mice because the ratio of delta to theta band power spectrum densities was greater in H1RKO mice than in wild-type mice. We concluded that histamine modulates ventilation by affecting metabolism and arousal state via H1 receptors.Key words: histamine type-1 receptor, metabolism, circadian pattern, arousal state, mice.The respiratory pattern is generated by the intrinsic cellular mechanisms and the network system of the respiratory neuron in the lower brain stem, which is affected by metabolic and behavioral control systems. During both awake and sleep stages, the metabolic control of respiration is always activated. However, in the awake stage respiration is influenced by various intrinsic or extrinsic environmental factors, such as thermal stress, pain, and various emotional changes. These behavioral controls are believed to be generated in the higher center rather than in the brain stem [1]. It is especially important that the hypothalamus, which plays a role in the regulation of the autonomic nervous system, responds to the environmental factors. Histaminergic neurons modulate many physiological functions, such as the arousal state [2,3], locomotor activity [4], feeding and drinking [5,6], lipid metabolism [7], and circadian rhythm [8,9]. These functions are closely related to changes in ventilation and are predominantly mediated by histamine type-1 (H1) receptors rather than type-2 (H2) receptors. To date, postsynaptic H1 and H2 receptors and presynaptic type-3 autoreceptors, have been identified in the brain [10]. Histaminergic neuronal cell bodies are located in the tuberomammillary nucleus of the posterior hypothalamus and project ascending and descending axons to much of the b...

Modulation of behavior by the histaminergic system: Lessons from HDC-, H3R- and H4R-deficient mice

“…Moreover, electroencephalography in Hdc −/− mice demonstrates increased power density of cortical ␦-waves, but reduced power density of cortical rhythm during wakefulness, as compared to wild-type controls (Parmentier et al, 2002). This may be a consequence of missing H 1 R activation in Hdc −/− mice, since an increased ␦/ wave ratio during the dark phase has also been found in Hrh1 −/− mice, which was interpreted as a state of reduced arousal (Ishiguro et al, 2006).…”

Effects of fasting on hypoxic ventilatory responses and the contribution of histamine H1 receptors in mice

“…We previously studied the metabolic rate throughout a 24-h measurement period under normoxic conditions. H1RKO mice show higher R values than WT mice, suggesting a predominance of glycolytic metabolism [42]. This metabolic trait was thought to be advantageous for anaerobic metabolism during hypoxia.…”

Time-Dependent Ventilatory Response to Poikilocapnic Hypoxia during Light and Dark Periods and the Role of Histamine H1 Receptors in Mice

“…Ventilation endogenously oscillates throughout the day, similar to metabolism and other physiological variables [1,2]. In nocturnal animals such as rodents, ventilation and metabolism are higher in the dark period than in the light one.…”

“…In earlier studies, we observed biphasic ventilatory responses to normocapnic hypoxia in mice. We added 3% CO 2 to the hypoxic gas to maintain a constant level of arterial PCO 2 (PaCO 2 ) [2,4,7]; this prevents hypocapnia induced by hypoxic hyperventilation [8]. Indeed, our previous blood gas analyses in mice showed PaCO 2 levels of 36-39 mmHg at 10 min after 7% O 2 inhalation adding 3% CO 2 [4, 9], but 19 mmHg at the same time after 7% O 2 inhalation [10].…”

“…Initial increases in ventilation were augmented during dark periods. H1 receptors had no major relationship with circadian variation, but affected the declined phase.Key words: histamine, ventilation, circadian variation.Ventilation endogenously oscillates throughout the day, similar to metabolism and other physiological variables [1,2]. In nocturnal animals such as rodents, ventilation and metabolism are higher in the dark period than in the light one.…”