Selective Histamine Research Articles

Effects of thioperamide on seizure development and memory impairment induced by pentylenetetrazole-kindling epilepsy in rats

Background Histamine H3 receptor antagonists have been considered as potential drugs to treat central nervous system diseases. However, whether these drugs can inhibit epileptogenesis remains unclear. This study aimed to investigate the effects of thioperamide, a selective and potent histamine H3 receptor antagonist, on the seizure development and memory impairment induced by pentylenetetrazole (PTZ)-kindling epilepsy in rats. Methods Chemical kindling was elicited by repeated intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35 mg/kg) once every 48 hours for 12 times, and seizure activity of kindling was recorded for 30 minutes. Control rats were ip injected with saline instead of PTZ. Morris water maze was used to evaluate the spatial memory. Phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) was tested by Western blotting in hippocampus. Results Intracerebroventricular (icv) injections with thioperamide (10 μg, 20 μg) 30 minutes before every PTZ injections, significantly prolonged the onset of PTZ-kindling and inhibited the seizure stages. PTZ-kindling seizures led to the impairment of spatial memory in rats, and thioperamide ameliorated the impairment of spatial learning and memory. Compared to non-kindling rats, there was a significant decrease in p-CREB level in hippocampus of the PTZ-kindling rats, which was reversed by thioperamide. Conclusions Thioperamide plays a protective role in seizure development and cognitive impairment of PTZ-induced kindling in rats. The protection of thioperamide in cognitive impairment is possibly associated with the enhancement of CREB-dependent transcription.

Histamine contributes to increased RANKL to osteoprotegerin ratio through altered nuclear receptor 4A activity in human chondrocytes

To elucidate histamine receptor-mediated signaling pathways, transcriptional events, and target gene expression in human cartilage. Histamine modulation of cartilage destruction was assessed by Safranin O staining and proteoglycan release. H(1) , H(2) , H(3) , and H(4) histamine receptor-dependent regulation of transcription factors (nuclear receptor 4A1 [NR4A1], NR4A2, and NR4A3), RANKL, and osteoprotegerin (OPG) messenger RNA (mRNA) levels were measured in primary and SW-1353 chondrocyte cells using quantitative polymerase chain reaction and selective histamine receptor antagonists. Soluble RANKL and OPG protein levels were determined using enzyme-linked immunosorbent assays. NR4A protein levels and transactivity were evaluated by Western blot analysis, immunocytochemistry, and luciferase reporter assays. Stable depletion of NR4A1-3 was achieved by lentiviral transduction of NR4A short hairpin RNA. Primary human chondrocyte cells expressed differential steady-state levels of H(1) -H(4) histamine receptor mRNA. In combination with tumor necrosis factor α, histamine significantly promoted cartilage proteoglycan depletion and release. Histamine modulated the expression of NR4A1-3 orphan receptors in primary and immortalized human chondrocyte cells in a time- and concentration-dependent manner. Histamine selectively signaled through H(1) and H(2) histamine receptors in chondrocytes to modulate RANKL and NR4A2 expression. The temporal effects of histamine on NR4A2 gene transcription were reduced in cells pretreated with inhibitors directed against protein kinase A, MAPK, and NF-κB signaling pathways. Histamine modulated the expression of RANKL with modest effects on OPG levels, leading to increased RANKL:OPG mRNA and protein ratios. Stable knockdown of NR4A1-3 expression resulted in reduced endogenous OPG levels and the loss of histamine-dependent regulation of RANKL expression. Our findings indicate that histamine, via H(1) and H(2) histamine receptors, contributes to joint disease by enhancing the ratio of RANKL to OPG expression through altered NR4A activity in human chondrocyte cells.

Histamine Excites Rat Superior Vestibular Nuclear Neurons via Postsynaptic H1 and H2 Receptors in vitro

The superior vestibular nucleus (SVN), which holds a key position in vestibulo-ocular reflexes and nystagmus, receives direct hypothalamic histaminergic innervations. By using rat brainstem slice preparations and extracellular unitary recordings, we investigated the effect of histamine on SVN neurons and the underlying receptor mechanisms. Bath application of histamine evoked an excitatory response of the SVN neurons, which was not blocked by the low-Ca²⁺/high-Mg²⁺ medium, indicating a direct postsynaptic effect of the amine. Selective histamine H₁ receptor agonist 2-pyridylethylamine and H₂ receptor agonist dimaprit, rather than VUF8430, a selective H₄ receptor agonist, mimicked the excitation of histamine on SVN neurons. In addition, selective H₁ receptor antagonist mepyramine and H₂ receptor antagonist ranitidine, but not JNJ7777120, a selective H₄ receptor antagonist, partially blocked the excitatory response of SVN neurons to histamine. Moreover, mepyramine together with ranitidine nearly totally blocked the histamine-induced excitation. Immunostainings further showed that histamine H₁ and H₂ instead of H₄ receptors existed in the SVN. These results demonstrate that histamine excites the SVN neurons via postsynaptic histamine H₁ and H₂ receptors, and suggest that the central histaminergic innervation from the hypothalamus may actively bias the SVN neuronal activity and subsequently modulate the SVN-mediated vestibular functions and gaze control.

Czy jest miejsce w pediatrii dla leków antyhistaminowych I generacji?

The first generation antihistamines because of the numerous side effects associated with the lack of selective histamine receptor interaction and the ability to penetrate the central nervous system in the treatment of allergic diseases have been replaced by a newer generation of drugs without these actions. In Poland, but also in many other countries the first generation antihistamines are still used in the treatment of vomiting and coughing. The paper presents the characteristics of the most commonly used the first generation antihistamines and the current indications for use of this drug in children.

Novel Medication Targets for the Treatment of Alcoholism: Preclinical Studies

Alcoholism is a complex heterogeneous disease and a number of neurotransmitter and neuromodulator systems have been implicated in its manifestation. Consequently, it is unlikely that existing medications such as disulfiram (Antabuse®), naltrexone (ReVia®), acamprosate (Campral®)) can be efficacious in every individual. Thus, the development of novel therapeutic agents with greater selectivity and less unwanted effects for the treatment of this disease is one of the major objectives of alcohol research. This review summarizes the findings of five novel compounds with different neuronal targets for treating alcoholism. These compounds include sazetidine-A, which selectively desensitizes α4β2 nicotinic receptors; carisbamate, a novel anti-epileptic agent; JNJ5234801, a novel anxiolytic agent; GS-455534, a highly selective inhibitor of mitochondrial aldehyde dehydrogenase; and JNJ-39220675, a selective histamine H3 antagonist. Inbred alcohol-preferring rats (iP), Fawn-Hooded (FH) rats, and P rats were used to evaluate the compounds. Naltrexone was used as a positive control in some experiments. All five compounds reduced alcohol consumption and preference. The mechanisms thought to underlie these effects suggest that, in addition to dopaminergic and opioidergic systems, other neuronal systems such as sodium channels (carisbamate), mitochondrial aldehyde dehydrogenase (GS-455534), 5-HT2 receptors (JNJ-5234801), histamine H3 receptors (JNJ-39220675), and α4β2 nicotinic receptors (sazetidine-A) can be involved in alcohol drinking. Further work is necessary to confirm the exact mechanisms of action of each drug and to determine any viable targets for putative treatment of alcohol-use disorders. The article presents some promising patents on novel medication targets for the treatment of alcoholism.

Synthesis of constrained benzocinnolinone analogues of CEP-26401 (irdabisant) as potent, selective histamine H3 receptor inverse agonists

A novel class of benzocinnolinones analogs of irdabisant were designed and synthesized as histamine H3R antagonists/inverse agonists. Modifications to the pyridazinone portion of the core and linker led to the identification of molecules with excellent target potency and selectivity with improved rat pharmacokinetic properties and reduced potential hERG liabilities.

Olopatadine ophthalmic solution suppresses substance P release in the conjunctivitis models

BackgroundOlopatadine hydrochloride ophthalmic solutions are treated for allergic conjunctival diseases that are a selective histamine H1 receptor antagonist and an inhibitor of the release of mediators including histamine from the human mast cells. Substance P (SP) levels are increased in tears of patients with allergic conjunctivitis. However, little is known about the regulation of SP release by anti-allergic ophthalmic solutions.ObjectiveWe investigated that the effect of olopatadine hydrochloride ophthalmic solutions (olopatadine 0.1% and olopatadine 0.2%) on rat conjunctivitis models compared with other anti-allergic ophthalmic solutions.MethodsConjunctivitis was induced by subconjunctival injection of histamine or intravenous injection of ovalbumin in rats passively sensitized with anti-ovalbumin anti-serum. The releases of SP were determined in the conjunctiva and tears using rat antigen-induced conjunctivitis models.ResultsOlopatadine 0.1% and 0.2% significantly inhibited the increased conjunctival dye leaked in the histamine- or antigen-induced hyperpermeability. The inhibitory effects by olopatadine were more potent than by other tested anti-allergic ophthalmic solutions. Moreover, olopatadine significantly inhibited the release of SP from the conjunctiva.ConclusionThese results indicate that olopatadine ophthalmic solutions appear to exert additional SP release inhibition besides dual-action such as selective histamine H1 receptor antagonistic action and mast cell stabilization action.

Preclinical Pharmacology of Desloratadine, a Selective and Nonsedating Histamine H1 Receptor Antagonist2nd Communication: Lack of central nervous system and cardiovascular effects

Desloratadine (descarboethoxyloratadine, CAS 100643-71-8) is a selective histamine H1 antagonist that exhibits qualitatively similar pharmacodynamic activity to its parent, loratadine (CAS 79794-75-5), but is 2.5-4 times more potent orally. In studies of central nervous system (CNS) effects that might lead to sedation, desloratadine had no behavioral, neurological or autonomic effects in the conscious mouse and rat. At large multiples of the antihistaminic dose in the mouse, it did not inhibit convulsions caused by electroconvulsive shock and inhibited acetic acid-induced writhing only at a dose approximately 1,000 times the antihistaminic dose in the mouse. Desloratadine had no effects on blood pressure, heart rate or electrocardiographic parameters in the rat or guinea pig or on electrocardiographic parameters in the monkey. Notably, there was no effect on the corrected Q-wave to T-wave (QTc) interval. Desloratadine did not inhibit IKr channel human ether-a-go-go-related gene (HERG)-induced current in a study in which HERG was expressed in Xenopus oocytes. In the rat, desloratadine did not cause effects in urine volume, electrolytes or creatinine, or inhibit gastric emptying or intestinal transit, or cause any harmful effects on gastric mucosa. The results of these preclinical studies provide evidence that desloratadine is a safe antihistamine without CNS or cardiovascular effects.

Properties of Olopatadine Hydrochloride, a New Antiallergic/Antihistamine Drug

Olopatadine hydrochloride (CAS 140462-76-6, KW-4679, AL-4943A; hereinafter referred to as olopatadine) is a novel antiallergic drug that is a selective histamine H1 receptor antagonist possessing inhibitory effects on the release of inflammatory lipid mediators such as leukotriene and thromboxane from human polymorphonuclear leukocytes and eosinophils. Olopatadine also inhibits the tachykininergic contractions in guinea pig bronchi by prejunctional inhibition of peripheral sensory nerves. Oral administration of olopatadine at doses of 0.03 mg/kg or higher reduces the symptoms of experimental allergic cutaneous responses and rhinoconjunctivitis in sensitized animals. Preclinical and clinical evaluations have demonstrated that olopatadine is a safe drug. After oral administration to healthy volunteers, olopatadine was rapidly and extensively absorbed. Unlike most other antiallergic drugs which are eliminated via hepatic metabolism, olopatadine is mainly excreted into urine. Olopatadine did not affect cytochrome P450 activities in human liver microsomes and consequently drug-drug metabolic interactions are unlikely. In double-masked clinical trials, olopatadine was shown to be effective at alleviating symptoms of allergic diseases. The drug (Allelock) was approved in Japan for the treatment of allergic rhinitis, chronic urticaria, eczema dermatitis, prurigo, cutaneous pruritus, psoriasis vulgaris and erythema exsudativum multiforme in December, 2000. An ophthalmic solution of olopatadine is also useful for the treatment of allergic conjunctivitis: this formulation (Patanol) was approved in the USA and the European Union for the treatment of seasonal and perennial allergic conjunctivitis in 1996 and 2002, respectively.

Optimization of 5-Pyridazin-3-one Phenoxypropylamines as Potent, Selective Histamine H3 Receptor Antagonists with Potent Cognition Enhancing Activity

Previous studies have shown that (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2 had high affinity for both the human (hH(3)R K(i) = 2.8 nM) and rat H(3)Rs (rH(3)R K(i) = 8.5 nM) but displayed low oral bioavailability in the rat. Optimization of the 5-pyridazin-3-one R(2) and R(6) positions to improve the pharmacokinetic properties over 2 led to the identification of 5-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2-pyridin-2-yl-2H-pyridazin-3-one 29. Compound 29 displayed high affinity for both human and rat H(3)Rs (hH(3)R K(i) = 1.7 nM, rH(3)R K(i) = 3.7 nM) with a greater than 1000-fold selectivity over the other histamine receptor subtypes and favorable pharmacokinetic properties across species (F = 78% rat, 92% dog, 96% monkey). It showed low binding to human plasma proteins, weakly inhibited cytochrome P450 isoforms, and displayed an excellent safety profile for a CNS-active compound. 29 displayed potent H(3)R antagonist activity in the brain in a rat dipsogenia model and demonstrated enhancement of cognitive function in a rat social recognition model at low doses. However, the development of compound 29 was discontinued because of genotoxicity.

Synthesis and structure–activity relationship of 5-pyridazin-3-one phenoxypiperidines as potent, selective histamine H3 receptor inverse agonists

Optimization of the R(2) and R(6) positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H-pyridazin-3-one 8b as a potent, selective histamine H(3) receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H(3)R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model.

Synthesis of novel histamine H4 receptor antagonists

This letter describes the discovery and synthesis of a series of octahydropyrrolo[3,4-c]pyrrole based selective histamine hH4 receptor antagonists. The amidine compound 20 was found to be a potent and selective histamine H4 receptor antagonist with moderate clearance and a high volume of distribution.

Health-related quality of life assessed by the effect of bepotastine besilate in patients with pruritus: Importance of emotions score in atopic dermatitis

The Skindex-16 questionnaire was recently developed as a measure of dermatological health-related quality of life (HRQoL), including symptoms, emotions and functional aspects. Bepotastine besilate is a selective histamine H(1) -receptor antagonist and a second-generation non-sedating antihistamine to treat various dermatological disorders. We assessed changes of the HRQoL instrument (Skindex-16) on patients with pruritus, including those with atopic dermatitis (AD) over bepotastine treatment period. The patients' personal assessment of the intensity of pruritus was determined using the Visual Analog Scale (VAS) for pruritus. Patients answered the Skindex-16 at baseline and at week 4. Forty-eight of 51 enrolled dermatological patients completed the Skindex-16. Of the 48 patients, 11 had AD and 37 had other conditions. Improvement in the clinical evaluation and VAS score was significant in all patients, the AD group and the other disorders group between baseline and week 4. Skindex-16 showed significantly lower scores for each of the three scales (symptoms, emotions and functioning) and the global score at baseline compared to that at week 4 in all patients and the other disorders. In contrast, there was a significant reduction in the emotions and global score among the AD patients. We found a significant correlation between falls in emotions score of Skindex-16 and falls in VAS scores for pruritus in the AD group. Bepotastine could be effective in the management of patients' HRQoL and useful in patients suffering with pruritus. We suggested that pruritus of AD patients could exert a stronger emotional effect due to the skin condition compared to the symptomatic or functional effects.

Pharmacological characterization of GSK1004723, a novel, long‐acting antagonist at histamine H1and H3receptors

Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H(1) and H(3) receptor antagonist. GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography. In cell membranes over-expressing human recombinant H(1) and H(3) receptors, GSK1004723 displayed high affinity, competitive binding (H(1) pKi = 10.2; H(3) pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t(1/2) of 1.2 and 1.5 h for H(1) and H(3) respectively. GSK1004723 specifically antagonized H(1) receptor mediated increases in intracellular calcium and H(3) receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H(1) and H(3) receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L(-1) ) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL(-1) intranasal) antagonized the histamine-induced response with a duration of up to 72 h. GSK1004723 is a potent and selective histamine H(1) and H(3) receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis.

Arrhythmogenic Effect of Sympathetic Histamine in Mouse Hearts Subjected to Acute Ischemia

The role of histamine as a newly recognized sympathetic neurotransmitter has been presented previously, and its postsynaptic effects greatly depended on the activities of sympathetic nerves. Cardiac sympathetic nerves become overactivated under acute myocardial ischemic conditions and release neurotransmitters in large amounts, inducing ventricular arrhythmia. Therefore, it is proposed that cardiac sympathetic histamine, in addition to norepinephrine, may have a significant arrhythmogenic effect. To test this hypothesis, we observed the release of cardiac sympathetic histamine and associated ventricular arrhythmogenesis that was induced by acute ischemia in isolated mouse hearts. Mast cell-deficient mice (MCDM) and histidine decarboxylase knockout (HDC(-/-)) mice were used to exclude the potential involvement of mast cells. Electrical field stimulation and acute ischemia-reperfusion evoked chemical sympathectomy-sensitive histamine release from the hearts of both MCDM and wild-type (WT) mice but not from HDC(-/-) mice. The release of histamine from the hearts of MCDM and WT mice was associated with the development of acute ischemia-induced ventricular tachycardia and ventricular fibrillation. The incidence and duration of induced ventricular arrhythmias were found to decrease in the presence of the selective histamine H(2) receptor antagonist famotidine. Additionally, the released histamine facilitated the arrhythmogenic effect of simultaneously released norepinephrine. We conclude that, under acute ischemic conditions, cardiac sympathetic histamine released by overactive sympathetic nerve terminals plays a certain arrhythmogenic role via H(2) receptors. These findings provided novel insight into the pathophysiological roles of sympathetic histamine, which may be a new therapeutic target for acute ischemia-induced arrhythmias.

Excitatory effect of histamine on rat spinal motoneurons by activation of both H1 and H2 receptors in vitro

The central histaminergic nervous system, originating from the tuberomammillary nucleus of the hypothalamus, widely innervates almost the whole brain as well as the spinal cord. However, the effect of histamine on spinal motoneurons, the final common path for motor control, is still unknown. By using 8-14-day-old rat spinal slice preparations and intracellular recordings, the effect of histamine on motoneurons in lumbar spinal cord and the underlying mechanisms were studied. Bath application of histamine (30-300 μM) induced a membrane depolarization in the majority of recorded spinal motoneurons (78/90, 86%). Perfusing slices with tetrodotoxin or low-Ca(2+) /high-Mg(2+) medium did not block the histamine-induced excitation, indicating a direct postsynaptic action of histamine on motoneurons. Separate application of the selective histamine H(1) receptor antagonist mepyramine or the selective histamine H(2) receptor antagonist ranitidine partially suppressed the histamine-induced excitation, whereas a combination of ranitidine and mepyramine totally blocked the excitatory effect of histamine on motoneurons. On the other hand, both the selective histamine H(1) receptor agonist 2-pyridylethylamine and the selective histamine H(2) receptor agonist dimaprit mimicked the excitation of histamine on spinal motoneurons. These agonist-induced excitations were also blocked by mepyramine or ranitidine. Furthermore, histamine affected membrane input resistance and potentiated repetitive firing behavior of spinal motoneurons. These results demonstrate that histamine excites rat spinal motoneurons via the histamine H(1) and H(2) receptors and increases their excitability, suggesting that the hypothalamospinal histaminergic fibers may directly modulate final motor outputs and actively regulate ongoing motor execution andspinal motor reflexes.

Selective histamine H3 and H4 receptor agonists exert opposite effects against the gastric lesions induced by HCl in the rat stomach

The present study investigated the role of histamine H(3) and H(4) receptors in gastric mucosal defense, by the use of selective ligands. Firstly, the affinities of several histaminergic agonists for the rat histamine H(3) and H(4) receptors were checked in HEK 293T cells transfected with either receptor subtype. Next, functional activities were determined in conscious rat against the ulcerogenic effect of 0.6N HCl. Radioligand binding studies showed that immethridine and methimepip were the most selective agonists at rat H(3) receptors, whereas VUF10460 displayed approximately a 50-fold selectivity for the rat H(4) receptor over the H(3) receptor. In conscious rats, immethridine and methimepip significantly reduced (66% and 48% inhibition, respectively) the gastric lesions induced by HCl; the effect of immethridine was antagonized by the H(3) receptor antagonist A-331440, but not by the H(4) receptor antagonist JNJ7777120. The mixed H(3)/H(4) receptor agonist immepip induced a significant aggravation of HCl damage, which was prevented by JNJ7777120; HCl-induced lesions were also significantly enhanced by the H(4) receptor agonists VUF10460 and VUF8430; however, this effect was not modified by JNJ7777120. Overall, this study indicates that, whereas the histamine H(3) receptor is involved in the protection of rat stomach against concentrated HCl, the functional role of the H(4) receptor is still to be defined, although selective agonists induce proulcerogenic effects under HCl challenge. Finally, the species-dependent variations in affinity and receptor selectivity observed for most ligands need to be carefully addressed in the pharmacological characterization of histamine H(3) and H(4) receptor functions in vivo.

Identification of pyridazin-3-one derivatives as potent, selective histamine H3 receptor inverse agonists with robust wake activity

H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.

Histamine H3 Receptor Agonists Decrease Hypothalamic Histamine Levels and Increase Stereotypical Biting in Mice Challenged with Methamphetamine

The effects of the histamine H(3) receptor agonists (R)-α-methylhistamine, imetit and immepip on methamphetamine (METH)-induced stereotypical behavior were examined in mice. The administration of METH (10 mg/kg, i.p.) to male ddY mice induced behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing (1.9%), circling (1.7%), sniffing (14.3%), and biting (82.1%). Pretreatment with (R)-α-methylhistamine (3 and 10 mg/kg, i.p.) significantly decreased stereotypical sniffing, but increased stereotypical biting induced by METH, in a dose-dependent manner. This effect of (R)-α-methylhistamine on behavior was mimicked by imetit or immepip (brain-penetrating selective histamine H(3) receptor agonists; 10 mg/kg, i.p. for each drug). Hypothalamic histamine levels 1 h after METH challenge were significantly increased in mice pretreated with saline. These increases in histamine levels were significantly decreased by pretreatment with histamine H(3) receptor agonists, effects which would appear to underlie the shift from METH-induced stereotypical sniffing to biting.

Histamine Elevates Free Intracellular Calcium in Mouse Retinal Dopaminergic Cells via H1-Receptors

Previously, retinopetal axons containing histamine and dopaminergic neurons expressing histamine H(1)-receptor had been localized in mouse retinas using anatomic techniques. The goal of these experiments was to demonstrate that these receptors are functional. Dopaminergic cells were acutely isolated from retinas of transgenic mice expressing red fluorescent protein under control of the tyrosine hydroxylase promoter and loaded with the calcium indicator Fura-2. Under control conditions, there were spontaneous oscillations in the levels of free intracellular calcium in dopaminergic cells. These oscillations were abolished in nominally calcium-free extracellular medium and in 1 μM tetrodotoxin, findings suggesting that the oscillations were mediated by calcium entry across the plasma membrane in response to sodium-dependent action potentials. Histamine increased the mean free intracellular calcium in the dopaminergic cells by increasing the frequency and/or amplitude of the calcium oscillations. The effects of histamine were dose-dependent and reached maximum at 5 μM. With this dose, there was a 65% increase in the mean free intracellular calcium concentration. The histamine H(1)-receptor antagonist, pyrilamine, blocked the effects of 5 μM histamine when applied at 50 μM. The selective histamine H(1)-receptor agonists, 2-(3-trifluoromethylphenyl) histamine and methylhistaprodifen significantly increased mean free intracellular calcium when applied at 5 μM. Histamine released from retinopetal axons in the mouse retina can elevate intracellular calcium levels in the perikarya of dopaminergic cells via the activation of histamine H(1)-receptors.