Central Histamine H1 Receptors Research Articles

Targeting the Central Histamine H2 Receptor: New Hope for Schizophrenia?

Targeting the Central Histamine H2 Receptor: New Hope for Schizophrenia?

The skeletal muscle relaxer cyclobenzaprine is a potent non‐competitive histamine H1 receptor antagonist

Cyclobenzaprine (Flexeril®) is a tricyclic dimethylpropanamine skeletal muscle relaxant that is used clinically to decrease muscle spasm and hypercontractility, without altering homeostatic muscle function. Although the absolute mechanism of action of cyclobenzaprine is unknown, it acts centrally to reduce tonic somatic motor function, likely via modulation of serotonergic and/or noradrenergic systems. While cyclobenzaprine is effective as a muscle relaxant, greater than 30% of patients experience drowsiness and sedative effects, yet, the mechanisms that cause these side effects are also undescribed. Based on this common adverse effect profile and the structural similarity of cyclobenzaprine to tricyclic antidepressants, we hypothesized that cyclobenzaprine facilitates sedative effects via off-target antagonism of central histamine H1 receptors (H1R). Here, for the first time, we present data that demonstrate that cyclobenzaprine exhibits low nanomolar affinity for the cloned human H1R, as well as that expressed in both rat and mouse brain. Using saturation binding experiments, our results demonstrate that cyclobenzaprine binds to the H1R in a non-competitive manner. Finally, using functional Ca+2 influx assays and novel TRUPATH BRET sensors, we show that cyclobenzaprine also blocks histamine-mediated H1R functional activity in a non-competitive manner. Given that cyclobenzaprine readily crosses the blood-brain barrier and its muscle relaxant effects occur centrally, our data suggest that off-target central antagonism of H1R by cyclobenzaprine facilitate the significant sedative effect of this agent seen in patients.

Hypothermia in mouse is caused by adenosine A1 and A3 receptor agonists and AMP via three distinct mechanisms

Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1−/−, Adora3−/−) mice. Confirming prior data, stimulation of the A3 adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H1 receptors. In contrast, A1AR agonists and AMP both acted centrally to cause hypothermia. Commonly used, selective A1AR agonists, including N6-cyclopentyladenosine (CPA), N6-cyclohexyladenosine (CHA), and MRS5474, caused hypothermia via both A1AR and A3AR when given intraperitoneally. Intracerebroventricular dosing, low peripheral doses of Cl-ENBA [(±)-5'-chloro-5'-deoxy-N6-endo-norbornyladenosine], or using Adora3−/− mice allowed selective stimulation of A1AR. AMP-stimulated hypothermia can occur independently of A1AR, A3AR, and mast cells. A1AR and A3AR agonists and AMP cause regulated hypothermia that was characterized by a drop in total energy expenditure, physical inactivity, and preference for cooler environmental temperatures, indicating a reduced body temperature set point. Neither A1AR nor A3AR was required for fasting-induced torpor. A1AR and A3AR agonists and AMP trigger regulated hypothermia via three distinct mechanisms.

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors.

Adenosine can induce hypothermia, as previously demonstrated for adenosine A1 receptor (A1AR) agonists. Here we use the potent, specific A3AR agonists MRS5698, MRS5841, and MRS5980 to show that adenosine also induces hypothermia via the A3AR. The hypothermic effect of A3AR agonists is independent of A1AR activation, as the effect was fully intact in mice lacking A1AR but abolished in mice lacking A3AR. A3AR agonist-induced hypothermia was attenuated by mast cell granule depletion, demonstrating that the A3AR hypothermia is mediated, at least in part, via mast cells. Central agonist dosing had no clear hypothermic effect, whereas peripheral dosing of a non-brain-penetrant agonist caused hypothermia, suggesting that peripheral A3AR-expressing cells drive the hypothermia. Mast cells release histamine, and blocking central histamine H1 (but not H2 or H4) receptors prevented the hypothermia. The hypothermia was preceded by hypometabolism and mice with hypothermia preferred a cooler environmental temperature, demonstrating that the hypothermic state is a coordinated physiologic response with a reduced body temperature set point. Importantly, hypothermia is not required for the analgesic effects of A3AR agonists, which occur with lower agonist doses. These results support a mechanistic model for hypothermia in which A3AR agonists act on peripheral mast cells, causing histamine release, which stimulates central histamine H1 receptors to induce hypothermia. This mechanism suggests that A3AR agonists will probably not be useful for clinical induction of hypothermia.

The role of the central histaminergic receptors in the exercise-induced improvements of the spatial learning and memory in rats

While it is well known that exercise can improve cognitive performance, the underlying mechanisms are not fully understood. There is now evidence that histamine can modulate learning and memory in different types of behavioral tasks. The present study was designed to examine the possible role of central histamine H1 and H2 receptors in forced treadmill running-induced enhancement of learning and memory in rats. For this purpose the animals received intracerebroventricularly chlorpheniramine (H1 receptor blocker) and cimetidine (H2 receptor blocker) before each day of fifteen consecutive days of exercise. Then their learning and memory were tested on the water maze task using a four-trial-per-day for 4 consecutive days. A probe trial was performed after the last training day. Our data showed that cimetidine reversed the exercise-induced improvement in learning and memory in rats; however, this was not the case regarding chlorpheniramine. Our findings indicate that central histamine H2 receptors play an important role in mediating the beneficial effects of forced exercise on learning and memory.

Sleep and Anesthesia

Sleep and Anesthesia

Analytical method for simultaneously measuring ex vivo drug receptor occupancy and dissociation rate: Application to (R)-dimethindene occupancy of central histamine H1 receptors

We introduce a novel experimental method to determine both the extent of ex vivo receptor occupancy of administered compound and its dissociation rate constant (k4). [Here, we reference k4 as the rate of offset of unlabeled ligand in convention with Motulsky and Mahan ()]. We derived a kinetic rate equation based on the dissociation rate constant for an unlabeled compound competing for the same site as a labeled compound and describe a model to simulate fractional occupancy. To validate our model, we performed in vitro kinetics and ex vivo occupancy experiments in rat cortex with varying concentrations of (R)-dimethindene, a sedating antihistamine. Brain tissue was removed at various times post oral administration, and histamine H1 receptor ligand [3H]-doxepin binding to homogenates from drug-treated or vehicle-treated rats was measured at multiple time points at room temperature. Fractional occupancy and k4 for (R)-dimethindene binding to H1 receptors were calculated by using our proposed model. Rats dosed with 30 and 60 mg/kg (R)-dimethindene showed 42% and 67% occupancy of central H1 receptors, respectively. These results were comparable to occupancy data determined by equilibrium radioligand binding. In addition, drug k4 rate determined by using our ex vivo method was equivalent to k4determined by in vitro competition kinetics (dissociation half-life t1/2 ~ 30 min). The outlined method can be used to assess, by simulation and experiment, occupancy for compounds based on dissociation rate constants and contributes to current efforts in drug optimization to profile antagonist efficacy in terms of its kinetic drug-target binding parameters. Data described by the method may be analyzed with commercially available software. Suggested fitting procedures are given in the appendix.

Histamine ameliorates anti-glomerular basement membrane antibody-induced glomerulonephritis in rats

Anti-glomerular basement membrane (anti-GBM)-induced glomerulonephritis involves T-helper type 1 (Th1) responses leading to rapid crescent formation. As many inflammatory and immune responses in general are affected by histamine, we examined the effects of histaminergic ligands on immune renal injury in the rat. Female Wistar-Kyoto rats were injected intraperitoneally with an antibody against the GBMs. Histaminergic ligands were then injected twice daily for 5 days after which renal function was assessed by proteinuria. Treatment with histamine led to significant dose-dependent reductions in proteinuria compared to the control antibody-injected group and markedly decreased the number of crescentic glomeruli and macrophage infiltration of the glomeruli. Furthermore, histamine significantly decreased the plasma concentration of interleukin-12, a Th1-type cytokine compared to the antibody-injected control animals. Dimaprit, an H(2)/H(4) agonist, mimicked the effects of histamine on proteinuria and crescent formation. Clozapine, an H(4) agonist, tended to mimic the effects of histamine, whereas an H(1), mepyramine, or an H(2) antagonist, ranitidine, did not reverse the protective effect of histamine. We suggest that histamine may alleviate renal injury in anti-GBM glomerulonephritis by suppressing the immune response.

Histamine H1 Blocker Hydroxyzine Improves Sleep in Patients With Cirrhosis and Minimal Hepatic Encephalopathy: A Randomized Controlled Pilot Trial

Sleep difficulty is common in minimal hepatic encephalopathy (HE) and the mechanisms are not fully elucidated. Dysregulated histamine neurotransmission is associated with an altered circadian rhythmicity that is partially restored following central histamine H1 receptor blockade in cirrhotic animals. We studied the effects of the histamine H1 blocker hydroxyzine in sleep alterations in patients with cirrhosis in a double-blind, randomized controlled fashion. A total of 35 patients (age 56 yr [36-69], Pugh's score 9 [7-12], portosystemic shunt: N = 7) with minimal HE and long-standing sleep difficulties (8 months [4-48]) and free from benzodiazepines were randomized to hydroxyzine 25 mg at bedtime (N = 17) or placebo (N = 18) for a 10-day period. Measurements of sleep behavior using visual analog scale and wrist actigraphy, neuropsychological tests, and protein s100beta serum levels were performed at baseline and at day 10. Subjective improvement in sleep was observed in 40% of hydroxyzine-treated patients but in none receiving placebo (P < 0.04). Objectively, 65% of hydroxyzine-treated patients versus 25% of patients under placebo had a >or=30% increase in sleep efficiency as measured by wrist actigraphy (P < 0.04). Neuropsychological tests (Z scores) and protein s100beta levels remained statistically unchanged in both groups. One patient developed an acute episode of encephalopathy reversible upon cessation of hydroxyzine. In contrast to placebo, hydroxyzine 25 mg at bedtime improved sleep behavior (subjectively and using wrist actigraphy) in patients with cirrhosis and minimal HE. The risk of precipitating overt HE warrants some caution when prescribing this drug.

Lack of temperature-induced polypnea in histamine H1 receptor-deficient mice

Breathing patterns are influenced by body temperature. However, the central mechanism for changes of breathing patterns is unknown. We previously showed that central histamine contributed to temperature-induced polypnea in mice (Izumizaki, M., Iwase, M., Homma, I., Yanai, K., Watanabe, T. and Watanabe, T., Central histamine contributed to the temperature-induced polypnea in mice, Neurosci. Res., 23 (1999) S282). In this study we examined the role of central histamine H1 receptors in temperature-induced polypnea using wild and mutant mice lacking histamine H1 receptors. Breathing patterns were characterized at two different body temperatures during hypercapnia under conscious conditions. In wild mice a raised body temperature increased respiratory frequency mainly due to a reduction in expiratory time, whereas in mutant mice respiratory frequency did not increase even though the body temperature was elevated. These results indicate that central histamine contributes to an increase in respiratory frequency due to a reduction in expiratory time through histamine H1 receptors when body temperature is raised.

The non-cardiac systemic side-effects of antihistamines: ebastine.

Ebastine and its active metabolite carebastine show potent antagonism of histamine H1-mediated phenomena in a wide variety of in vitro and in vivo non-clinical experimental models. By contrast, activity is not seen against histamine H2- or H3-mediated, nor acetylcholine- or serotonin-mediated phenomena, and both compounds are virtually without effect in models measuring pharmacological effects on the central nervous system (CNS). Explanation of these observations is found in their high selectivity for the histamine H1 receptor and in their low in vivo potency in displacing [3H]-mepyramine from central histamine H1 receptors, indicating that they do not readily pass the blood-brain barrier. These findings have been mirrored in clinical experimental models where oral doses of ebastine (1-30 mg) showed clear dose-related inhibition of intradermal histamine-induced weal and flare responses, whereas doses of 90 mg were without anticholinergic effects on salivary flow, cardiovascular reflexes or pilocarpine-induced miosis. Furthermore, in an extensive series of controlled studies in specific clinical models for measuring objective effects on the CNS, ebastine in single doses of 10-90 mg and repeated doses of 10-30 mg once daily, had no clinically relevant effects on cognitive performance and visual co-ordination tests, nor on simulated car-tracking tests and real car-driving tests. Nor was their any interaction with ethanol or diazepam. On subjective test parameters (questionnaires and visual analogue scales) there were only a few isolated and random incidences of minor increases in some indices of sedation at the highest doses. Not surprisingly, therefore, the clear therapeutic benefit seen during the extensive and international use of ebastine (5-20 mg once daily) in the treatment of seasonal and perennial rhinitis and chronic idiopathic urticaria, has not been accompanied by signs of drug-induced anticholinergic effects (dry mouth, disturbances of visual accommodation) or sedation, making it an effective and well-tolerated first-line treatment alternative to other second-generation antihistamines.

Food Intake Is Inversely Correlated with Central Nervous System Histamine Receptor (H1) Concentrations in Male Sprague-Dawley Rats Fed Normal, Low Protein, Low Energy or Poor Quality Protein Diets

The reported studies were designed to examine relationships between whole-brain histamine receptors (H1) and food intake in male Sprague-Dawley rats. Three different experiments were conducted. In each experiment, control rats were fed normal protein (25 g casein/100 g food) and normal metabolizable energy (16.21 kJ/100 g food) diets. Feeding low protein diets (1 g casein/100 g food) elevated central H1 receptor concentrations (P < 0.0027) and reduced voluntary food intake (P < 0.007) compared with normal diets. Feeding low energy diets lowered H1 receptor concentrations (P < 0.0089) and increased voluntary food intake (P < 0.0012). Low quality protein diets also affected the central nervous histaminergic system. Whole-brain H1 receptor concentrations were significantly higher for rats fed low quality protein (25 g gelatin/100 g food) compared with rats fed casein (P < 0.0001). Rats fed medium quality protein (25 g wheat gluten/100 g food) or low quality protein ate significantly less food (P < 0.0001). In all experiments, dietary manipulation affected central histamine receptors. Elevated concentrations of H1 receptors were associated with a decrease in food intake whereas lowered concentrations of H1 receptors were associated with an increase in food intake (P < 0.001). The results of these experiments support the hypothesis that central histamine H1 receptor concentrations in male rats are inversely correlated with voluntary food intake and affected by dietary composition.

Pituitary-adrenocortical responsiveness to histaminergic stimulation during social stress of crowding in rats

Social stress of crowding for 3, 7, 14 and 21 days drastically reduces the serum corticosterone response to intracerebroventricular administration of dimaprit, a histamine H2-receptor agonist, moderately diminishes the response to pyridylethylamine, an H1-receptor agonist, and does not change significantly the corticosterone response to histamine. These results suggest that social stress of crowding considerably desensitizes central histamine H2-receptors involved in stimulation of the hypothalamic-pituitary-adrenal axis.

Arterial baroreceptors and brain histamine contribute to bradycardia to peripheral hyperosmolality.

The purpose of this study was to determine whether the bradycardic response to peripheral hyperosmolality in conscious rats is dependent on afferent baroreceptor mechanisms and whether central histamine H2 receptors play a role in baroreflex-mediated changes in heart rate (HR). Mean arterial pressure (MAP) and HR were recorded continuously during a 30-min infusion of 2.5 M NaCl (10 microliters.100 g-1.min-1) hypertonic saline (HTS). HTS infusion significantly increased MAP (21 +/- 4 mmHg) and reduced HR (-62 +/- 10 beats/min) in rats with intact arterial baroreceptors. In sinoaortic-denervated rats, HR remained unchanged from control despite a significant increase in MAP. After intracerebroventricular (lateral ventricle) administration of cimetidine or ranitidine (H2-receptor antagonists) in intact rats, HTS infusion significantly increased MAP (19 +/- 2 and 17 +/- 2 mmHg, respectively) but the bradycardia was abolished (-12 +/- 10 and -10 +/- 10 beats/min, respectively). In contrast, central H2-receptor blockade did not alter reflex HR responses to the intravenous administration of phenylephrine and nitroprusside or to the central administration of histamine or angiotensin II. These results indicate that the bradycardic response to HTS infusion is mediated through the arterial baroreceptor reflex and involves in part a selective histaminergic pathway.

Characterization of central H2 receptors mediating cardiovascular activity by means of three histamine H2 receptor antagonists: MK-208, BMY-25368, and cimetidine in the rat

Stimulation of central histamine H1 and or H2 receptors with histaminergic drugs results in a dose-related pressor response and bradycardia in conscious, freely-moving rats. Two recently developed peripheral histamine H2 antagonists, MK-208 and BMY-26368, as well as cimetidine, were evaluated with respect to their ability to block the cardiovascular actions of central histamine H2 receptors. These drugs do not readily cross the blood brain barrier, therefore, they were administered intracerebroventricularly (i.c.v.). The ability of these agents to attenuate the cardiovascular effects of the H2 agonist impromidine was studied in conscious, freely-moving rats. Blood pressure and heart rate were monitored directly via indwelling carotid catheters, and drugs were administered i.c.v. through permanently implanted cannulae. All of the H2 antagonists tested induced a transient hypertensive response that lasted approximately 15 min. MK-208 (30 μg) partially blocked the central cardiovascular actions of impromidine. Unlike other histaminergic agents, MK-208 produced a tachycardia and a profound hyperactivity which slowly developed into seizures. BMY-25368 and cimetidine failed to antagonize the cardiovascular actions of impromidine. These results demonstrate that cimetidine and BMY-25368, established peripheral H2 antagonists, did not block central H2 receptors, suggesting that central and peripheral H2 receptors may be pharmacologically distinct.

Evidence for central histaminergic mechanism in foot shock aggression

The role of central histaminergic system in foot shock induced aggression was studied in mice. Histamine administered by intracerebral (IC) injection (25-200 micrograms) produced a significant increase in fighting episodes in a dose dependent manner. It was observed that mepyramine (H1 blocker) given intraperitoneally (IP) significantly increased and metiamide (H2 blocker) given IC decreased significantly the fighting response. To determine the nature of receptors involved in histamine induced facilitation of aggressive behaviour, histamine was administered IC in mice pretreated with mepyramine or metiamide. Mepyramine pretreatment further increased the facilitatory effect of histamine while metiamide blocked the enhancement of aggressiveness by histamine. Combined pretreatment with metiamide and mepyramine decreased significantly the fighting counts which remained unaffected after histamine. Haloperidol did not block the enhancement of aggression by histamine or mepyramine. However, atropine pretreatment partially inhibited the histamine induced increase in the fighting counts. Results of pretreatment with metiamide and atropine were similar to those obtained with pretreatment of metiamide and mepyramine. Metiamide alone or in combination with atropine failed to affect the facilitatory effect of amphetamine on the foot-shock aggression. It is concluded that central histamine H2 receptors have a facilitatory role and H1 receptors an inhibitory role on aggressive behaviour in mice induced by foot-shock. Since histamine per se had a facilitatory effect on foot-shock induced aggression, the central H2 receptors seem to dominate over the H1 receptors.

Central hypotensive effects of imidazole acetic acid and rolipram (ZK 62 711) in rats

In urethane-anaesthetized rats the administration of imidazole acetic acid (IAA), 34–272 μg per rat intracerebroventricularly (i.c.v.), induced a dose-related fall in blood pressure. Rolipram (ZK 62 711), a potent and selective inhibitor of cyclic AMP phosphodiesterase (cAMP-PDE), also lowered the blood pressure in a dose-dependent manner when administered at the doses of 1–64 μg per rat i.c.v. A subhypotensive dose of rolipram (0.25 μg per rat i.c.v.) did not change the hypotensive effect of IAA. Pretreatment of the rats with metiamide, 1.1. mg per rat i.c.v., shifted the dose-response curve for IAA significantly to the right. The present results make it unlikely that the central hypotensive effect of IAA could be due to the stimulation of cAMP-PDE by this agent. Central histamine H2-receptors may be involved in the hypotensive effect of IAA.

Possible involvement of central histamine H2-receptors in the hypotensive effect of clonidine.

CLONIDINE and some other antihypertensive drugs exert their effect by acting on the central nervous system1–4. Some α-adrenoceptor blocking drugs antagonise the centrally mediated hypotensive effect of clonidine5–7. It has therefore been suggested that clonidine acts by stimulating central α-adrenoceptors, bringing about a depression of the cardiovascular system. The involvement of classical α-adreno-ceptors has, however, been challenged8,9. Moreover, in the brain tissue clonidine may even be a potent α-adrenoceptor antagonist10.