Specific Inhibitor Of Histidine Decarboxylase Research Articles

Histamine promotes mouse decidualization through stimulating epithelial amphiregulin release.

Accumulating evidence shows that inflammation is essential for embryo implantation and decidualization. Histamine, a proinflammatory factor that is present in almost all mammalian tissues, is synthesized through decarboxylating histidine by histidine decarboxylase (HDC). Although histamine is known to be essential for decidualization, the underlying mechanism remains undefined. In the present study, histamine had no obvious direct effects on in vitro decidualization in mice. However, the obvious differences in HDC protein levels between day 4 of pregnancy and day 4 of pseudopregnancy, as well as between delayed and activated implantation, suggested that the blastocyst may be involved in regulating HDC expression. Furthermore, blastocyst-derived tumor necrosis factor α (TNFα) significantly increased HDC levels in the luminal epithelium. Histamine increased the levels of amphiregulin (AREG) and disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) proteins, which was abrogated by treatment with famotidine, a specific histamine type 2 receptor (H2R) inhibitor, or by TPAI-1 (a specific inhibitor of ADAM17). Intraluminal injection of urocanic acid (HDC inhibitor) on day 4 of pregnancy significantly reduced the number of implantation sites on day 5 of pregnancy. TNFα-stimulated increases in HDC, AREG and ADAM17 protein levels was abrogated by urocanic acid, a specific inhibitor of HDC. Additionally, AREG treatment significantly promoted in vitro decidualization. Collectively, our data suggests that blastocyst-derived TNFα induces luminal epithelial histamine secretion, and histamine increases mouse decidualization through ADAM17-mediated AREG release.

Involvement of central histaminergic and cholinergic systems in the morphine-induced increase in blood-brain barrier permeability to sodium fluorescein in mice

Morphine (5 mg/kg, s.c.) caused a submaximal increase in the brain level of sodium fluorescein administered i.v. Histamine H1-antagonists, diphenhydramine and mepyramine, given either i.p. or i.c.v., had no significant influence on the effect of morphine. H2-Antagonists, cimetidine and ranitidine, administered i.c.v., but not i.p., significantly inhibited the morphine effect. alpha-Fluoromethylhistidine, a specific histidine decarboxylase inhibitor (given i.p. and i.c.v.) and antimuscarinic drugs, atropine and biperiden, but not methylatropine (given i.p.) also significantly reduced the morphine effect. Physostigimine (i.p.) significantly enhanced the effects of 0.5 and 1 mg/kg of morphine. Similar effects of histaminergic and cholinergic drugs were also observed on the buprenorphine- and DAGO-induced increase in blood-brain barrier (BBB) permeability to sodium fluorescein. None of the treatments with 6-hydroxydopamine, alpha-methyltyrosine, 5,7-dihydroxytryptamine or p-chlorophenylamine had any significant effect on the morphine-induced increase in BBB permeability. These findings suggest that the activation of brain H2-receptors by neuronal histamine and muscarinic receptors by acetylcholine is involved in the increase in BBB permeability to sodium fluorescein caused by mu opioid receptor agonists.

Involvement of central histaminergic neurons in polypnea induced by hyperthermia in rabbits

A role of central histamine in the preoptic area/anterior hypothalamus (POA/AH) for the regulation of hyperthermia-induced polypnea was examined in anesthetized, paralyzed, vagotomized and artificially ventilated rabbits. Phrenic nerve activities were recorded to monitor respiratory neuronal output. Hyperthermia increased respiratory frequency by reductions of inspiratory time ( T I) and expiratory time ( T E). Pyrilamine, an H1 receptor antagonist, which was applied to the POA/AH reduced polypnea under hyperthermia. The effect of S(+)α-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, applied in a lateral ventricle was comparable to the effect of pyrilamine on polypnea. Moreover, histamine dihydrochloride applied into the POA/AH at a normal body temperature produced polypnea by reductions of T I and T E. The results suggest that central histamine in the POA/AH contributes to the generation of polypnea in hyperthermia through H1 receptors.

Central histamine contributed to temperature-induced polypnea in mice

Breathing pattern is influenced by body temperature. However, the central mechanism for changing breathing patterns is unknown. Central histamine is involved in heat loss mechanisms in behavioral studies, but little is known about its effect on breathing patterns. We examined first the effect of body temperature on breathing patterns with increasing hypercapnia in conscious mice and then that of the depletion of central histamine by S(+)-alpha-fluoromethylhistidine hydrochloride (alpha-FMH) (100 mg/kg ip), a specific inhibitor of histidine decarboxylase, at normal and raised body temperatures. A raised body temperature increased respiratory frequency with reductions in both inspiratory and expiratory time and decreased tidal volume. On the other hand, alpha-FMH lowered respiratory frequency with a prolongation of expiratory time at the raised temperature; however, this was not observed at a normal temperature. These results indicate that central histamine contributes to an increase in respiratory frequency as a result of a reduction in expiratory time when body temperature is raised.

Depletion of brain histamine induced by α -fluoromethylhistidine enhances radial maze performance in rats with modulation of brain amino acid levels

We examined the effects of repeated administration of (S)- α- fluoromethylhistidine (FMH), a specific inhibitor of histidine decarboxylase (HDC), on radial maze performance and brain contents of histamine and amino acids in rats. By daily subcutaneous (s.c.) administration of FMH (100 mg kg ), rats showed significant enhancement of a radial maze performance without changes in locomotion. Six days after FMH treatment, the histamine levels both in the cerebral cortex and diencephalon decreased significantly. However, the glutamate and glycine levels significantly increased in the cerebral cortex and hippocampus. These results suggest that FMH enhances the acquisition phase of radial maze study with the increases in glutamate and glycine levels in the cerebral cortex and hippocampus of rats.

Lack of a precursor-product relationship between histamine and its metabolites in brain after histidine loading.

Levels of histamine and its major metabolites in brain, tele-methylhistamine (t-MH) and tele-methylimidazoleacetic acid (t-MIAA), were measured in rat brains up to 12 h after intraperitoneal administration of L-histidine (His), the precursor of histamine. Compared with saline-treated controls, mean levels of histamine were elevated at 1 h (+102%) after a 500 mg/kg dose; levels of t-MH did not increase. Following a 1,000 mg/kg dose, mean histamine levels were increased for up to 7 h, peaked at 3 h, and returned to control levels within 12 h. In contrast, levels of t-MH showed a small increase only after 3 h; levels of t-MIAA remained unchanged after either dose. Failure of most newly formed histamine to undergo methylation, its major route of metabolism in brain, suggested that histamine was metabolized by another mechanism possibly following nonspecific decarboxylation. To test this hypothesis, other rats were injected with alpha-fluoromethylhistidine (alpha-FMHis; 75 mg/kg, i.p.), an irreversible inhibitor of specific histidine decarboxylase. Six hours after rats received alpha-FMHis, the mean brain histamine level was reduced 30% compared with saline-treated controls. Rats given His (1,000 mg/kg) 3 h after alpha-FMHis (75 mg/kg) and examined 3 h later had a higher (+112%) mean level of histamine than rats given alpha-FMHis, followed by saline. Levels of t-MH and t-MIAA did not increase. These results imply that high doses of His distort the simple precursor-product relationship between histamine and its methylated metabolites in brain. The possibility that some His may undergo nonspecific decarboxylation in brain after His loading is discussed. These findings, and other actions of His independent of histamine, raise questions about the validity of using His loading as a specific probe of brain histaminergic function.

1659 Involvement of histamine h1 receptors on the polypnea induced by rising body temperature

A role of central histamine in the preoptic area/anterior hypothalamus (POA/AH) for the regulation of hyperthermia-induced polypnea was examined in anesthetized, paralyzed, vagotomized and artificially ventilated rabbits. Phrenic nerve activities were recorded to monitor respiratory neuronal output. Hyperthermia increased respiratory frequency by reductions of inspiratory time (TI) and expiratory time (TE). Pyrilamine, an H1 receptor antagonist, which was applied to the POA/AH reduced polypnea under hyperthermia. The effect of S(+)α-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, applied in a lateral ventricle was comparable to the effect of pyrilamine on polypnea. Moreover, histamine dihydrochloride applied into the POA/AH at a normal body temperature produced polypnea by reductions of TI and TE. The results suggest that central histamine in the POA/AH contributes to the generation of polypnea in hyperthermia through H1 receptors.

Long-term depletion of brain histamine induced by α-fluoromethylhistidine increases feeding-associated locomotor activity in mice with a modulation of brain amino acid levels

We examined the long-term effects of administration of ( S)-α-fluoromethylhistidine (FMH), a specific inhibitor of histidine decarboxylase, on the spontaneous locomotor activity, food intake and brain contents of histamine, catecholamines, serotonin and amino acids of ICR mice. The distance of ambulation and number of rearings significantly increased from 8 to 15 h (20.00-03.00 h) after treatment with FMH (100 mg/kg, i.p.) and the 24-h food intake also increased significantly. On FMH treatment, the locomotor activity in movements of 3–15 cm/0.5 s was greater than that of control mice, whereas the number of slight movements (0–1 cm/0.5 s) decreased, suggesting that once a mouse treated with FMH is in motion, it moves a longer distance than a control mouse. We sacrificed mice 12 or 24 h after FMH treatment to measure the brain contents of histamine, monoamines and amino acids. Decrease of the brain histamine content to 35% of the control level was observed until 24 h after FMH treatment, but no significant changes in the brain catecholamine and serotonin contents were detected. However, the brain GABA content of ICR mice decreased to 85% of control 12 h after FMH treatment. Moreover, decrease of the brain GABA content after FMH treatment was greater in mast cell-deficient W W v mice, being 70 and 62% of the control level 12 and 24 h after treatment, respectively. The present experiments support the idea that the locomotor activity is affected by the central histaminergic system, directly and/or indirectly.

Brain histaminergic system in mast cell-deficient (Ws/Ws) rats: histamine content, histidine decarboxylase activity, and effects of (S) alpha-fluoromethylhistidine.

The mast cell-deficient [Ws/Ws (White spotting in the skin)] rat was investigated with regard to the origin of histamine in the brain. No mast cells were detected in the pia mater and the perivascular region of the thalamus of Ws/Ws rats by Alcian Blue staining. The histamine contents and histidine decarboxylase (HDC) activities of various brain regions of Ws/Ws rats were similar to those of +/+ rats except the histamine contents of the cerebral cortex and cerebellum. As the cerebral cortex and cerebellum have meninges that are difficult to remove completely, the histamine contents of these two regions may be different between Ws/Ws and +/+ rats. We assume that the histamine content of whole brain with meninges in Ws/Ws rats is < 60% of that in +/+ rats. So we conclude that approximately half of the histamine content of rat brain is derived from mast cells. Next, the effects of (S) alpha-fluoromethylhistidine (FMH), a specific inhibitor of HDC, on the histamine contents and HDC activities of various regions of the brain were examined in Ws/Ws rats. In the whole brain of Ws/Ws rats, 51 and 37% of the histamine content of the control group remained 2 and 6 h, respectively, after FMH administration (100 mg/kg of body weight). Therefore, we suggest that there might be other histamine pools including histaminergic neurons in rat brain.

Aggregated IgE mimic interleukin-3-induced histamine synthesis by murine hematopoietic progenitors

Similar to interleukin-3 (IL-3), IgE acts on murine bone marrow cells by inducing histamine production. This effect does not result from degranulation of histamine-containing cells, but from histamine synthesis, as assessed by the following findings. (1) The histamine content of freshly isolated bone marrow cells is too low to account for the increase in extracellular histamine levels. (2) Neither IL-3 nor IgE induced histamine production in the presence of the specific inhibitor of histidine decarboxylase (HDC), the histamine-forming enzyme. (3) Both the enzymatic activity and the mRNA expression of HDC were enhanced in response to IL-3 or IgE. Artificial aggregation or formation of IgE immune complexes augmented ther effect on histamine synthesis, indicating that the aggregated form is responsible for this biologic activity. Yet, it is apparently not mediated by Fc epsilon RI because their cross-linkage by dinitrophenyl bovine serum albumin after presensitization with IgE did not induce histamine production by hematopoietic progenitors. Among other aggregated isotypes tested, only IgG2a and, to a lesser extent, IgG1 had a consistent but lower effect, whereas IgM and IgA were completely inactive. The target cells of IL-3 and IgE in terms of histamine synthesis do not belong to mature bone marrow populations, especially mast cells. They copurify with hematopoietic progenitors in the low-density layers of a discontinuous Ficoll gradient where they represent around 5% of the cells, as determined by in situ hybridization. This percentage remained the same, regardless of whether the cells were stimulated by IgE or IL-3 alone or by a combination of both, suggesting a common responder cell. In accordance with this notion, histamine-producing cells could not be distinguished from each other on the basis of density, size and internal structure, or rhodamine (Rh) retention. Finally, the effect of IgE is not caused by the induction of IL-3 because anti-IL-3 antibodies did not abrogate the effect of IgE.

Aggregated IgE Mimic Interleukin-3-Induced Histamine Synthesis by Murine Hematopoietic Progenitors

Similar to interleukin-3 (IL-3), IgE acts on murine bone marrow cells by inducing histamine production. This effect does not result from degranulation of histamine-containing cells, but from histamine synthesis, as assessed by the following findings. (1) The histamine content of freshly isolated bone marrow cells is too low to account for the increase in extracellular histamine levels. (2) Neither IL-3 nor IgE induced histamine production in the presence of the specific inhibitor of histidine decarboxylase (HDC), the histamine-forming enzyme. (3) Both the enzymatic activity and the mRNA expression of HDC were enhanced in response to IL-3 or IgE. Artificial aggregation or formation of IgE immune complexes augmented ther effect on histamine synthesis, indicating that the aggregated form is responsible for this biologic activity. Yet, it is apparently not mediated by Fc epsilon RI because their cross-linkage by dinitrophenyl bovine serum albumin after presensitization with IgE did not induce histamine production by hematopoietic progenitors. Among other aggregated isotypes tested, only IgG2a and, to a lesser extent, IgG1 had a consistent but lower effect, whereas IgM and IgA were completely inactive. The target cells of IL-3 and IgE in terms of histamine synthesis do not belong to mature bone marrow populations, especially mast cells. They copurify with hematopoietic progenitors in the low-density layers of a discontinuous Ficoll gradient where they represent around 5% of the cells, as determined by in situ hybridization. This percentage remained the same, regardless of whether the cells were stimulated by IgE or IL-3 alone or by a combination of both, suggesting a common responder cell. In accordance with this notion, histamine-producing cells could not be distinguished from each other on the basis of density, size and internal structure, or rhodamine (Rh) retention. Finally, the effect of IgE is not caused by the induction of IL-3 because anti-IL-3 antibodies did not abrogate the effect of IgE.

From biochemistry to pharmacology: the histaminergic neuron system in the brain

The histaminergic neuron system in the brain has been well-characterized in the last twenty years. This article describes the studies performed by our research groups and discusses the physiological functions of the histaminergic neurons. To demonstrate the distribution of neuronal antibodies against histidine decarboxylase (HDC), the sole enzyme responsible for histamine formation, was used, although the purification of the HDC from fetal rat liver was a difficult task. It took five years to purify the enzyme and another five years to obtain specific antibody suitable for immunohistochemistry. The cell bodies were located in the tuberomammillary nucleus of the posterior hypothalamus. The clusters of cell bodies were designated as E1-5 groups. The fibers that projected from the neurons were distributed in almost all parts of the brain, especially densely in the anterior hypothalamus. alpha-Fluoromethylhistidine, a specific inhibitor of HDC, is a powerful tool for reducing the neuronal histamine in the brain. Administration of alpha-fluoromethylhistidine led to changes in various activities of the brain such as arousal state, circadian rhythm, neuroendocrine functions, feeding behavior, body temperature, and vestibular function. These results indicate that the histaminergic neuron system regulates a wide range of physiological functions in the brain by targeting both neurons and glial cells, on which we found histamine H1 and H2 receptors. The molecular structure of the H1-receptor was also discussed.

GM‐CSF in association with IL‐1 triggers day‐8 CFU‐S into cell cycle: Role of histamine

Our recent evidence for the requirement of endogeneous histamine in IL-3-induced proliferation of day-8 CFU-S has prompted us to investigate whether or not GM-CSF, which shares with IL-3 the ability to stimulate bone marrow histamine synthesis, could also affect the cell cycle status of CFU-S via this mediator. We show herein that recombinant GM-CSF alone fails to trigger day-8 CFU-S into S phase, but supports their survival. However, in the same experimental conditions, GM-CSF in combination with IL-1 induces a CFU-S proliferation similar to that obtained in response to IL-3, while IL-1 by itself has no effect on this biological activity. We further provide evidence that this phenomenon is completely abolished: i) by preventing GM-CSF-induced histamine synthesis by alpha-FMH, the specific inhibitor of histidine decarboxylase (HDC), or ii) by blocking the binding sites of H2 histamine receptors with their specific antagonist oxmetidine. Similar results are obtained when progenitor-enriched bone marrow cells are used instead of the unfractionated population. In addition, we provide an argument in support of a histamine receptor modulation by GM-CSF that could explain the lack of effect of factor-induced histamine on day-8 CFU-S cell cycling. Indeed, the entry of these progenitors into S phase that is normally promoted by dimaprit, a specific histamine H2 receptor agonist, is abolished by a preincubation with GM-CSF. Taken together, our data support the conclusion that IL-1 makes CFU-S sensitive to GM-CSF-induced endogeneous histamine that will trigger them into cell cycle, while GM-CSF alone has no such effect on this biological activity.

Mediation of the Stress-Induced Prolactin Release by Hypothalamic Histaminergic Neurons and the Possible Involvement of Vasopressin in This Response*

We investigated the role of histamine (HA) in the neuroendocrine regulation of PRL secretion in conscious male rats. Blood samples were obtained by decapitation of the animals at 0 min. Intracerebroventricular infusion of HA (34-540 nmol at -15 min) stimulated PRL secretion dose dependently with an ED50 of approximately 135 nmol. Inhibition of neuronal HA synthesis by the specific histidine decarboxylase-inhibitor (S)alpha-fluoro-methylhistidine (alpha FMH; 100 mumol/kg ip at -6 h or 400 mumol/kg ip at -20 h and -6 h) caused a 50% reduction (P less than 0.01) in the PRL response to 5 min of restraint stress. Inhibition of neuronal HA metabolism by the specific histamine-methyltransferase-inhibitor SKF-91488 (400 and 800 nmol icv at -20 min) augmented the restraint stress-induced PRL release 26% and 37%, respectively (P less than 0.05). The two enzyme inhibitors had no or only modest effect on the basal PRL secretion. Pretreatment with a specific antiserum (0.5 ml) to arginine vasopressin (AVP) or an AVP antagonist (25 nmol) administered iv at -20 min inhibited the PRL response to HA (270 nmol icv) 80% and 45%, respectively (P less than 0.01) and inhibited the PRL response to restraint stress 70% (P less than 0.01). In contrast, pretreatment with a specific oxytocin (OT) antagonist (50 nmol) had no effect on the HA- or stress-induced PRL release. The AVP antiserum showed less than 0.0003% cross-reactivity with OT, and radiolabeled OT did not bind to serial dilutions of plasma from rats treated with the AVP antiserum. The AVP antiserum or the AVP antagonist almost prevented the PRL release induced by iv infusion of 800 pmol AVP or a posterior pituitary extract. Infusion of AVP (24-800 pmol iv at -15 min) stimulated PRL secretion dose dependently. However, the dose of AVP (800 pmol) required to induce an increase in plasma PRL similar to that obtained by HA-stimulation, led to a rise in plasma AVP which was approximately 1000-fold higher than that induced by HA, which increased plasma AVP 2-fold. Restraint stress had no effect on the plasma AVP level. We conclude that neuronal HA participates in the mediation of the PRL response to stress and that the stress- and HA-induced release of PRL may involve AVP, whereas an involvement of OT seems unlikely.(ABSTRACT TRUNCATED AT 400 WORDS)

?-Fluoromethylhistidine decreases the histamine content of the rat right atrium under the influence of sympathetic activity

alpha-Fluoromethylhistidine (alpha-FMH; 65 mg/kg, i.p.), a specific inhibitor of histidine decarboxylase, significantly decreased the histamine content of the rat right atrium in a time-dependent manner; the maximal decrease of 22.2% was observed 4 h after injection. However, alpha-FMH had no significant effect on the histamine content of the left atrium or the ventricles. The alpha-FMH-induced decrease in the right atrial histamine content was not observed in rats pretreated with 6-hydroxydopamine (25 mg/kg, i.p.). Two i.p. injections of 10 and 5 mg/kg of propranolol and the cardioselective beta 1-adrenoceptor antagonist metoprolol almost completely inhibited the alpha-FMH-induced histamine decrease. On the other hand, phentolamine (10 mg/kg, i.p.) had no influence on the histamine-decreasing action of alpha-FMH. These results suggest that in the rat right atrium there is a histamine pool where a rapid turnover of histamine is maintained by normal sympathetic activity.

Effects of Nociceptive Stimuli on Brain Histamine Dynamics

The effects of nociceptive stimuli on the metabolism of brain histamine (HA) were examined, because of a previous observation that the exposure of mice to electric foot shock increased the brain HA turnover. In mice, the exposure to tail pinch markedly increased the brain level of te/e-methylhistamine (t-MH), a predominant metabolite of brain HA, while the level of HA was not changed. The HA turnover, measured either by the accumulation of t-MH after pargyline injection or by the HA depletion after the treatment with a-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, was enhanced by the exposure to tail pinch, like the enhancement produced by the exposure to foot shock. The exposure of rats to tail pinch increased the t-MH level in the telencephalon and the midbrain. Other types of noxious stimuli, such as placing mice on a hot plate or subjecting mice to acetic acid-induced writhing, also significantly elevated the level of t-MH but not that of HA in the mouse brain. These results suggest that nociceptive stimuli produce an increase in the brain HA turnover.

Histamine Turnover in the Rat Hypothalamic Nuclei Estimated from α-Fluoromethylhistidine-lnduced Histamine Decrease

AbstractThe turnover rates, rate constants and half-life values of neuronal histamine (HA) in 10 nuclei of the rat hypothalamus were estimated from the depletion of HA induced by α-fluoromethylhistidine (α-FMH: 100 mg/kg. i.p). a specific inhibitor of histidine decarboxylase, on the presumption that α-FMH depletable HA pools represent neuronal ones. Marked variation in the HA turnover rates were observed among the hypothalamic nuclei, ranging from 5.7 to 19.5 pmole/mg protein/hr

Histamine turnover in the rat hypothalamic nuclei estimated from alpha-fluoromethylhistidine-induced histamine decrease.

The turnover rates, rate constants and half-life values of neuronal histamine (HA) in 10 nuclei of the rat hypothalamus were estimated from the depletion of HA induced by alpha-fluoromethylhistidine (alpha-FMH: 100 mg/kg, i.p.), a specific inhibitor of histidine decarboxylase, on the presumption that alpha-FMH depletable HA pools represent neuronal ones. Marked variation in the HA turnover rates were observed among the hypothalamic nuclei, ranging from 5.7 to 19.5 pmole/mg protein/hr.

Effects of nociceptive stimuli on brain histamine dynamics.

The effects of nociceptive stimuli on the metabolism of brain histamine (HA) were examined, because of a previous observation that the exposure of mice to electric foot shock increased the brain HA turnover. In mice, the exposure to tail pinch markedly increased the brain level of tele-methylhistamine (t-MH), a predominant metabolite of brain HA, while the level of HA was not changed. The HA turnover, measured either by the accumulation of t-MH after pargyline injection or by the HA depletion after the treatment with alpha-fluoromethylhistidine, a specific inhibitor of histidine decarboxylase, was enhanced by the exposure to tail pinch, like the enhancement produced by the exposure to foot shock. The exposure of rats to tail pinch increased the t-MH level in the telencephalon and the midbrain. Other types of noxious stimuli, such as placing mice on a hot plate or subjecting mice to acetic acid-induced writhing, also significantly elevated the level of t-MH but not that of HA in the mouse brain. These results suggest that nociceptive stimuli produce an increase in the brain HA turnover.

Histamine and related substances influence neurotransmission in the semicircular canal.

Histamine and other imidazole-containing substances were found to increase ampullar nerve afferent firing rate while both H1 and H2 histamine antagonists effectively inhibited ampullar nerve activity. A specific inhibitor of histidine decarboxylase, the enzyme which catalyses the synthesis of histamine, reduced ampullar nerve firing in a dose-dependent manner. These observations suggest a physiological role for histamine in the inner ear. Maintenance of a response to histamine after de-efferentation of the crista ampullaris supports the hypothesis that the site of action is the hair cell; antagonism of the histamine response by a cholinergic antagonist, atropine, and antagonism of a cholinergically mediated facilitation by the histaminergic antagonist pyrilamine, indicate that the site of action may involve the acetylcholine receptor complex on the crista ampullaris hair cells. The observation that imidazole-containing compounds cause significant effects on semicircular canal neurotransmission provides an important finding with regard to the site of action of antihistamines used for the treatment of vertigo and motion sickness.