Histamine Receptor Research Articles

Histamine and Its Receptors in the Mammalian Inner Ear: A Scoping Review.

Histamine is a widely distributed biogenic amine with multiple biological functions mediated by specific receptors that determine the local effects of histamine. This review aims to summarize the published findings on the expression and functional roles of histamine receptors in the inner ear and to identify potential research hotspots and gaps. A search of the electronic databases PubMed, Web of Science, and OVID EMBASE was performed using the keywords histamine, cochlea*, and inner ear. Of the 181 studies identified, 18 eligible publications were included in the full-text analysis. All four types of histamine receptors were identified in the mammalian inner ear. The functional studies of histamine in the inner ear were mainly in vitro. Clinical evidence suggests that histamine and its receptors may play a role in Ménière's disease, but the exact mechanism is not fully understood. The effects of histamine on hearing development remain unclear. Existing studies have successfully determined the expression of all four histamine receptors in the mammalian inner ear. However, further functional studies are needed to explore the potential of histamine receptors as targets for the treatment of hearing and balance disorders.

Antihistamines improve cardiovascular manifestations and other symptoms of long-COVID attributed to mast cell activation.

Long-COVID is a broadly defined condition and there are no effective therapies. Cardiovascular manifestations of long-COVID include high heart rate, postural tachycardia, and palpitations. Previous studies have suggested that mast cell activation (MCA) may play a role in the pathophysiology of long-COVID, including in the mechanisms of its cardiovascular manifestations. The present study aimed to evaluate the effectiveness of a treatment with blockers of histamine receptors in patients with long-COVID who did not respond to other therapies. In all, 14 patients (F/M = 9/5; 49.5 ± 11.5 years) and 13 controls (F/M = 8/5; 47.3 ± 8.0 years) with long-COVID symptoms attributed to MCA were evaluated. Patients were treated with fexofenadine (180 mg/day) and famotidine (40 mg/day). Fatigue, brain fog, abdominal disorders, and increased heart rate were evaluated in treated and untreated patients at baseline and 20 days later. Long-COVID symptoms disappeared completely in 29% of treated patients. There was a significant improvement in each of the considered symptoms (improved or disappeared) in all treated patients, and the improvement grade was significantly greater in treated patients compared to controls. No significant differences in the outcomes were observed in the controls. Our data confirm that histamine receptors blockade may be an effective target to successfully treat long-COVID. Our finding supports the underlying role of MCA in the pathophysiology of long-COVID.

Olanzapine manipulates neuroactive signals and may onset metabolic disturbances

Olanzapine is one of the most prescribed atypical antipsychotics to treat psychiatric illness and is associated with weight gain and metabolic disturbance. The present study investigated the olanzapine-regulated metabolic pathways using functional enrichent analysis including binding affinity with G-protein-coupled receptors (GPCRs). Proteins modulated by olanzapine were retrieved from SwissTargetPrediction, DIGEP-Pred, and BindingDB and then enriched in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to assess molecular function, biological process, and cellular components including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We used homology modeling to improve the 3D structure for GPCR synapse proteins including dopamine, serotonin, muscarinic, and histamine receptors which were then optimized using molecular dynamics (MD) simulations. The protein-olanzapine binding mechanisms for different GPCR binders were evaluated using molecular docking; later refined by MD simulations. Binding mechanism of olanzapine with D2, 5HT1A, 5HT2A, 5HT2B, 5HT2C, M1, and M2 receptors were created using homology modeling and optimized using MD simulations. In target identification, it was observed that olanzapine majority targeted G-protein coupled receptors. Further, enrichment analysis identified around 76% of the total genes regulated in molecular function, biological process, and cellular components were common including KEGG pathways. Moreover, it was observed that olanzapine had a major potency over the neurotransmitter synapse including neuroactive signals . Olanzapine-induced weight gain and metabolic alterations could be due to the deregulation of multiple synapses like dopamine, serotonin, muscarinic, and histamine at the feeding center followed by cGMP-PKG, cAMP, and PI3K-Akt signaling pathways. HIGHLIGHTS Olanzapine is used in the management of psychiatric illnesses. Olanzapine causes disturbance in lipids and glucosehomeostasis and manipulates energy expenditure. Olanzapine-induced weight gain may occur due to the deregulation of the multiple synapse and cGMP-PKG, cAMP, and PI3K-Akt signaling pathway Communicated by Ramaswamy H. Sarma

Lysergic acid diethylamide stimulates cardiac human H2 histamine and cardiac human 5-HT4-serotonin receptors

Lysergic acid diethylamide (LSD) is an artificial hallucinogenic drug. Thus, we hypothesized that LSD might act 5-HT4 serotonin receptors and/or H2 histamine receptors. We studied isolated electrically stimulated left atrial preparations, spontaneously beating right atrial preparations, and spontaneously beating Langendorff-perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of the human 5-HT4 receptor (5-HT4-TG) or of the H2-histamine receptor (H2-TG). For comparison, we used wild type littermate mice (WT). Finally, we measured isometric force of contraction in isolated electrically stimulated muscle strips from the human right atrium obtained from patients during bypass surgery. LSD (up to 10 µM) concentration dependently increased force of contraction and beating rate in left or right atrial preparations from 5-HT4-TG (n = 6, p < 0.05) in 5-HT4-TG atrial preparations. The inotropic and chronotropic effects of LSD were antagonized by 10 µM tropisetron in 5-HT4-TG. In contrast, LSD (10 µM) increased force of contraction and beating rate in left or right atrial preparations, from H2-TG. After pre-stimulation with cilostamide (1 µM), LSD (10 µM) increased force of contraction in human atrial preparations (n = 6, p < 0.05). The contractile effects of LSD in human atrial preparations could be antagonized by 10 µM cimetidine and 1 µM GR 125487. LSD leads to H2-histamine receptor and 5-HT4-receptor mediated cardiac effects in humans.

Histaminergic regulation of food intake.

Histamine is a biogenic amine that acts as a neuromodulator within the brain. In the hypothalamus, histaminergic signaling contributes to the regulation of numerous physiological and homeostatic processes, including the regulation of energy balance. Histaminergic neurons project extensively throughout the hypothalamus and two histamine receptors (H1R, H3R) are strongly expressed in key hypothalamic nuclei known to regulate energy homeostasis, including the paraventricular (PVH), ventromedial (VMH), dorsomedial (DMH), and arcuate (ARC) nuclei. The activation of different histamine receptors is associated with differential effects on neuronal activity, mediated by their different G protein-coupling. Consequently, activation of H1R has opposing effects on food intake to that of H3R: H1R activation suppresses food intake, while H3R activation mediates an orexigenic response. The central histaminergic system has been implicated in atypical antipsychotic-induced weight gain and has been proposed as a potential therapeutic target for the treatment of obesity. It has also been demonstrated to interact with other major regulators of energy homeostasis, including the central melanocortin system and the adipose-derived hormone leptin. However, the exact mechanisms by which the histaminergic system contributes to the modification of these satiety signals remain underexplored. The present review focuses on recent advances in our understanding of the central histaminergic system's role in regulating feeding and highlights unanswered questions remaining in our knowledge of the functionality of this system.

Ergometrine stimulates histamine H2 receptors in the isolated human atrium

Ergometrine (6aR,9R)-N-((S)-1-hydroxypropan-2-yl)-7-methyl-4,6,6a,7,8,9-hexa-hydro-indolo-[4,3-fg]chinolin-9-carboxamide or lysergide acid β-ethanolamide or ergonovine) activates several types of serotonin and histamine receptors in the animal heart. We thus examined whether ergometrine can activate human serotonin 5-HT4 receptors (h5-HT4R) and/or human histamine H2 receptors (hH2R) in the heart of transgenic mice and/or in the human isolated atrium. Force of contraction or beating rates were studied in electrically stimulated left atrial or spontaneously beating right atrial preparations or spontaneously beating isolated retrogradely perfused hearts (Langendorff setup) of mice with cardiac specific overexpression of the h5-HT4R (5-HT4-TG) or of mice with cardiac specific overexpression of the hH2R (H2-TG) or in electrically stimulated human right atrial preparations obtained during cardiac surgery. Western blots to assess phospholamban (PLB) phosphorylation on serine 16 were performed. Ergometrine exerted concentration- and time-dependent positive inotropic effects and positive chronotropic effects in atrial preparations starting at 0.3 µM and reaching a plateau at 10 µM in H2-TGs (n = 7). This was accompanied by an increase in PLB phosphorylation at serine 16. Ergometrine up 10 µM failed to increase force of contraction in left atrial preparations from 5-HT4-TGs (n = 5). Ten micrometer ergometrine increased the force of contraction in isolated retrogradely perfused spontaneously beating heart preparations (Langendorff setup) from H2-TG but not 5-HT4-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergometrine at 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, and these effects were eliminated by 10 µM of the H2R antagonist cimetidine but not by 10 µM of the 5-HT4R antagonist tropisetron. Furthermore, ergometrine showed binding to human histamine H2 receptors (at 100 µM and 1 mM) using HEK cells in a recombinant expression system (pKi < 4.5, n = 3). In conclusion, we suggest that ergometrine is an agonist at cardiac human H2Rs.

Tylophora indica (Burm. f.) Merr alleviates tracheal smooth muscle hyperresponsiveness in ovalbumin-induced allergic-asthma model in guinea-pigs: Evidences from ex vivo, in silico and in vivo studies.

Tylophora indica (Burm. f.) Merr is a climbing perennial plant reported in Indian traditional system of medicine for its use in allergy and asthma. However, only few scientific studies have been performed in the past to validate its antiasthmatic potential. The present study deals with investigation of airway smooth muscle relaxant and antiasthmatic potential of extract and subsequent fractions prepared from T.indica. The most active fraction of T.indica leaves selected through bio-guided activity was subjected to liquid chromatography-mass spectrometry (LC-MS) analysis for chemical profiling. The binding affinity of identified compounds in fraction towards M3 and H1 receptors was determined by molecular docking study. F-2 (chloroform fraction prepared from methanolic extract of T.indica leaves) was examined for its smooth muscle relaxant properties using isolated trachea of guinea-pig. Further, F-2 was evaluated through in vivo studies employing ovalbumin-induced asthma model in guinea-pigs. F-2 was found most effective in bioassay-guided fractionation. Characterization by LC-MS analysis revealed presence of five major bioactive compounds in F-2 that showed good docking interactions with M3 and H1 receptors. The ex vivo study demonstrated that F-2 could significantly relax tracheal rings via targeting multiple signalling pathways videlicet, namely, noncompetitive antagonism of the histamine and muscarinic receptors, β2-adrenergic stimulation and activation of soluble guanylyl cyclase. In in vivo studies, F-2 ameliorated airway hyperresponsiveness and decreased broncho alveolar lavage fluid (BALF) levels of inflammatory cytokines and immunoglobulin E (IgE). These results confirm the traditional use of T.indica as an antiasthmatic agent which are evidenced through ex vivo, in silico and in vivo studies.

The histamine system and cognitive function: An in vivo H3 receptor PET imaging study in healthy volunteers and patients with schizophrenia.

The histamine-3 receptor (H3R) is an auto- and heteroreceptor that inhibits the release of histamine and other neurotransmitters. Post-mortem evidence has found altered H3R expression in patients with psychotic disorders, which may underlie cognitive impairment associated with schizophrenia (CIAS). We used positron emission tomography (PET) imaging to compare brain uptake of an H3R selective tracer between patients with schizophrenia and matched controls (healthy individuals). Regions of interest included the dorsolateral prefrontal cortex (DLPFC) and striatum. We explored correlations between tracer uptake and symptoms, including cognitive domains. A total of 12 patients and 12 matched controls were recruited to the study and were assessed with psychiatric and cognitive rating scales. They received a PET scan using the H3R-specific radioligand [11C]MK-8278 to determine H3R availability. There was no statistically significant difference in tracer uptake between patients and controls in the DLPFC (t19 = 0.79, p = 0.44) or striatum (t21 = 1.18, p = 0.25). An exploratory analysis found evidence for lower volume of distribution in the left cuneus (pFWE-corrected = 0.01). DLPFC tracer uptake was strongly correlated with cognition in controls (trail making test (TMT) A: r = 0.77, p = 0.006; TMT B: rho = 0.74, p = 0.01), but not in patients (TMT A: r = -0.18, p = 0.62; TMT B: rho = -0.06, p = 0.81). These findings indicate H3R in the DLPFC might play a role in executive function and this is disrupted in schizophrenia in the absence of major alterations in H3R availability as assessed using a selective radiotracer for H3R. This provides further evidence for the role of H3R in CIAS.

PPIs and gastric cancer: any causal relationship?

Hydrochloric acid is crucial in gastric physiology. In 1978 cimetidine, the first H2 antagonist of histamine receptors on the gastric parietal cell was introduced into therapy, inducing acid. Lasting the years, several studies focused on the potential relationship between inducing hypo-achlorhydria and risk of developing gastric cancer. In 1988 omeprazole, the first proton pump inhibitor, entered therapy. In 1996, Kuipers underlined the danger of progression of chronic atrophic gastritis in subjects taking PPIs. In 2018, one paper from Korea and an another on from Sweden suggested a possible relationship between long-term PPI therapy and the development of gastric cancer. Over the years, several articles, meta-analyzes and population based focused on relationship between long-term of PPI use and the onset of gastric cancer, with conflicting results. As reported, the presence of bias in the collection of cases, in particular concerning the evaluation of the H.p. status and presence of atrophic gastritis and intestinal metaplasia in subjects treated with PPI, can lead to noticeable errors in the results and conclusions, as demonstrated in the literature by exhaustive methodological studies of pharmacoepidemiology. A possible bias in the collection of case histories is due to the fact that PPIs are often administered to dyspeptic patients, among which there are patients already carriers of gastric neoplasia: the so-called inverse causality. Literature data, amended by methodological bias (sampling errors, lack of comparative assessment of Hp status and atrophic gastritis) NOT support a causal relationship between long-term PPIs therapy and the onset of gastric cancer.

Is Quifenadine an antihistamine of the first generation? Do we know everything…

Quifenadine , a drug developed in the laboratory of M.D.Mashkovsky in the 1970s, is one of the first examples of the creation of a new class of nonsedative antihistamines of multifunctional action, combining high selective activity to block type 1 histamine receptors, the ability to block the action of serotonin and enhance histaminase activity in tissues. The article describes the latest data on the study of the pharmacokinetics of the drug, presents studies on the efficacy and safety of quifenadine. Currently, the question remains open to which generation of antihistamines to include quinuclidine, considering all the described characteristics.

Evaluation of the Level of Histamine 1 and 2 Receptors with Some Biochemical Variables in Patients with Hepatitis C Virus Infection

The current study was carried out at Ibn - Sina Hospital in Nineveh Governorate, where the relationship between histamine receptors1&amp;2, liver enzyme functions, Albumin, and Alkaline phosphate was studied in patients with hepatitis C virus type. Samples were taken from patients diagnosed with hepatitis C, 60 of whom were compared with 30 controls. Take 5ml of blood, separate it with a centrifuge, and test the serum. The sample size was equal for Men and Women, and the age range was 18 to 78 years. ALT (GPT), Albumin, Alkaline phosphates, and histamine-2 receptor levels were statistically significant, while AST (GOT) and histamine-1 receptor levels were not statistically significant.

Histamine H1- and H4-receptor expression in human colon-derived cell lines

In previous studies, we demonstrated the involvement of H4R in inflammatory bowel disease (IBD) and IBD-associated colon cancer in mice and could ascribe H4R-mediated histamine function to colon epithelial cells. The transferability of obtained data to humans is however lacking. Functional expression of H4R on colon epithelial cells is a prerequisite to pursue the hypothesis of involvement of H4R in carcinogenesis. Thus, we here compared the expression of histamine receptor subtypes in a series of cell lines. Out of these, three colon-derived cell lines displaying different combinations of H1R and H4R expression were submitted to functional analyses. Human hematopoietic HMC-1, HL-60, and U937, lung-derived A549 and Calu-3, and colorectal LoVo, SW 480, Caco-2, HT-29, and HCT116 cells were included in the study. mRNA expression was quantified by RT-qPCR. For functional analyses, Caco-2, HT-29, and HCT116 cells were treated by incubation with 1 – 10 µM histamine in the presence or absence of selective histamine receptor antagonists. Calcium mobilization, cAMP accumulation, and cell proliferation were measured by fluorimetry, mass spectrometry, and real-time bioimpedance measurements, respectively. Histamine receptor expression was heterogeneous in the cell lines tested. In most cell lines, we detected H1R mRNA while H4R mRNAs were found only occasionally. The colon-derived epithelial cell lines LoVo, SW480, and HT-29 expressed H1R mRNA exclusively, while in HCT116 cells H1R and H4R mRNAs and in CaCo-2 H2R mRNA were detectable. Subsequent functional analyses in HT29, Caco-2, and HCT116 cells, however, indicated that only HT-29 responded to histamine stimulation, by means of H1R. For a detailed analysis of histamine receptor function, esp. that of H1R and H4R, in human colon-derived cell lines, the cell lines tested here are not fully convenient unless genetically modified.

Regulatory Perspective Reverse Engineering Analysis of the Mast Cell Stabilizer and the Histamine Receptor Antagonist (Olopatadine HCl): Instrumental and Classical Methods for Multiple Formulations.

This study evaluates the unknown qualitative (Q1) and quantitative (Q2) formulas for nasal spray and ophthalmic solution formulations of olopatadine HCl by classical and instrumental techniques to match the generic formula with reference-listed drugs to avoid clinical study. Reverse engineering of olopatadine HCl nasal spray 0.6% and ophthalmic solution 0.1, 0.2% formulations was accurately quantified using a simple and sensitive reversed-phase high-performance liquid chromatography (HPLC) method. Both formulations possess similar components, namely ethylenediaminetetraacetic acid (EDTA), benzalkonium chloride (BKC), sodium chloride (NaCl), and dibasic sodium phosphate (DSP). These components were qualitatively and quantitatively determined using the HPLC, osmometry, and titration techniques. With derivatization techniques, EDTA, BKC, and DSP were determined by ion-interaction chromatography. NaCl in the formulation was quantified by measuring the osmolality and using the subtraction method. A titration method was also used. All the employed methods were linear, accurate, precise, and specific. The correlation coefficient was >0.999 for all components in all the methods. The recovery results ranged from 99.1 to 99.7% for EDTA, 99.1-99.4% for BKC, 99.8-100.8% for DSP, and 99.7-100.1% for NaCl. The obtained % relative standard deviation for precision was 0.9% for EDTA, 0.6% for BKC, 0.9% for DSP, and 1.34% for NaCl. The specificity of the methods in the presence of other components, diluent, and the mobile phase was confirmed, and the analytes were specific.

L-Anserine Increases Muscle Differentiation and Muscle Contractility in Human Skeletal Muscle Cells.

l-Anserine, an imidazole peptide, has a variety of physiological activities, but its effects on skeletal muscle differentiation and muscle contractile force remain unknown. Thus, in this study, we investigated the effect of l-anserine on muscle differentiation and muscle contractile force in human skeletal muscle cells. In two-dimensional culture, 1 μM l-anserine significantly increased the myotube diameters (26.5 ± 1.71, 27.7 ± 1.08, and 28.8 ± 0.85 μm with 0, 0.1, and 1 μM l-anserine, respectively) and the expression levels of genes involved in muscle differentiation and the sarcomere structure. In three-dimensional culture, 1 μM l-anserine significantly increased the contractile force of engineered human skeletal muscle tissues cultured on a microdevice (1.99 ± 0.30, 2.17 ± 0.62, 2.66 ± 0.39, and 3.28 ± 0.85 μN with 0, 0.1, 0.5, and 1 μM l-anserine, respectively). l-Anserine also increased the myotube diameters and the proportion of myotubes with sarcomere structures in the cultured tissues. Furthermore, the histamine receptor 1 (H1R) antagonist attenuated the l-anserine-induced increase in the contractile force, suggesting the involvement of H1R in the mechanism of action of l-anserine. This study showed for the first time that l-anserine enhances muscle differentiation and muscle contractility via H1R.

Activity Models of Key GPCR Families in the Central Nervous System: A Tool for Many Purposes.

G protein-coupled receptors (GPCRs) are targets of many drugs, of which ∼25% are indicated for central nervous system (CNS) disorders. Drug promiscuity affects their efficacy and safety profiles. Predicting the polypharmacology profile of compounds against GPCRs can thus provide a basis for producing more precise therapeutics by considering the targets and the anti-targets in that family of closely related proteins. We provide a tool for predicting the polypharmacology of compounds within prominent GPCR families in the CNS: serotonin, dopamine, histamine, muscarinic, opioid, and cannabinoid receptors. Our in-house algorithm, "iterative stochastic elimination" (ISE), produces high-quality ligand-based models for agonism and antagonism at 31 GPCRs. The ISE models correctly predict 68% of CNS drug-GPCR interactions, while the "similarity ensemble approach" predicts only 33%. The activity models correctly predict 56% of reported activities of DrugBank molecules for these CNS receptors. We conclude that the combination of interactions and activity profiles generated by screening through our models form the basis for subsequent designing and discovering novel therapeutics, either single, multitargeting, or repurposed.

AQUEOUS LEAF EXTRACT OF Ficus carica L. INHIBITS HISTAMINE INDUCED GASTRIC ACID SECRETION, WHILE PROMOTING INTESTINAL MOTILITY IN SPRAGUE DAWLEY RAT

Background: Ficus carica is a plant belonging to the family Moraceae, popularly known as ‘Opoto’ in Southwest Nigeria. It is used in folk medicine as an emollient, demulcent, laxative and galactogogue. However, these claims need to be scientifically evaluated. In this study, the effects of oral administration of the aqueous leaf extract of Ficus carica L. on gastric acid acidity and intestinal motility were studied in laboratory rats. Objectives: The objectives of this study are to evaluate the effect of aqueous leaf extracts of Ficus carica on gastric acid secretion and intestinal motility in the laboratory rats. Method: The research was divided into two phase; gastric acid secretion and gastric motility studies. A total of forty-two male rats used for this study were divided into two groups; group for gastric secretion study (10 rats) and those rats for intestinal motility study (32 rats). The groups were further divided into control and extract treated group and the latter were gavaged with 2.0 mg/kg of the extract daily for three week prior to the assay while the control group received equal volume of distilled for the duration of the study. Animals were fasted overnight before the day of the test. The motility study was carried out using the activated charcoal method while the effect on gastric acid secretion was carried out by gastric effluent titration method at basal rate and after the administration of histamine and histamine receptor blocker respectively. Results: Aqueous Ficus carica L. leaf extracts significantly reduced gastric acidity while reducing the gastrointestinal transit time with increased peristaltic index. Conclusion: Aqueous leaf extract of Ficus carica reduced the acidity of the gastric secretion while increasing the motility. This extract may further be explored for possible development of drugs for treating gastric ulcer and constipation.

Pediatric Gastroesophageal Reflux Disease (GERD): A Literature Review

Background: Gastroesophageal reflux disease (GERD) is a condition where stomach contents reflux into the esophagus, causing discomfort and complications. It is most prevalent in infants (26.9%) and lesser in children under 10 (3.2%) and over 10 years old (10.1%). Discussion: GERD is caused by frequent relaxations of the lower esophageal sphincter (LES), allowing stomach contents to escape into the esophagus. Symptoms vary with age, with infants experiencing regurgitation and irritability, while older children may have heartburn and nausea. Diagnosis requires differentiating GERD from similar conditions and may involve various tests, though their primary use lacks sufficient evidence. Nonpharmacological treatments include thickened feeding, reducing feeding volume but increasing frequency and possibly eliminating cow's milk protein. Pharmacological treatments include Proton Pump Inhibitors (PPIs), and Histamine Receptor Antagonists (H2RAs), though their efficacy varies. Prokinetics are generally not recommended due to lack of evidence. If all these treatments fail, anti-reflux surgery such as fundoplication can be considered. Conclusion: The hallmark of GERD is the presence of esophagitis during endoscopy. However, Barrett’s esophagus is rare in pediatric GERD patients. Factors indicating a worse prognosis include early onset age, an initial GERD diagnosis, and the need for PPI or combination of H2RA and PPI treatment.

1020 Modafinil Induced Psychosis

Abstract Introduction Modafinil has been used for the treatment of numerous different conditions, including daytime somnolence (EDS). Modafinil is a non-amphetamine central nervous system (CNS) stimulant with wakefulness-promoting properties. There have been few reported cases of psychosis associated with modafinil use, however a large majority of those were seen in patients with a history of primary psychiatric disturbances. Report of case(s) We present a case of a 48 year old female coming for evaluation of excessive daytime somnolence. She completed polysomnography and a multi sleep latency test (MSLT) which revealed mildly elevated AHI, but no sleep onset rapid eye movements (SOREMPs). A diagnosis of idiopathic hypersomnia was subsequently made and 200mg of modafinil up to twice daily was prescribed for her. Patient initially tolerated the modafinil well, however she began having delusions and she subsequently required psychiatric evaluation. These delusions primarily consisted of her believing she was under surveillance and had conspiracy theories against her. She also described having auditory hallucinations as well, especially voices telling her about these conspiracy theories. She also demonstrated poor insight into her medical condition as she refused to discontinue modafinil. Upon evaluation, routine labs including complete blood count, chemistry profile and urine drug screens were completed to rule out any secondary causes of psychosis. It was therefore recommended by psychiatry to discontinue modafinil as there was concern that the delusions were occurring secondary to medication use. The patient's psychotic delusions seemed to dissipate after this. A multidisciplinary meeting was held regarding management of patients' excessive daytime sleepiness (EDS) and a decision was made to begin the patient on pitolisant, a histamine receptor antagonist. The patient was able to achieve great benefit with this medication. Conclusion The presented case illustrates a patient who began having psychosis after beginning modafinil 200mg twice daily. Psychosis is a much more rare side of modafinil and providers should become aware of it. Therefore, patients who are prescribed modafinil should be carefully followed for psychosis development, even when they are previously healthy and have no history of any primary psychiatric conditions. Support (if any)

Additive effect of histamine and muscimol upon induction of antinociceptive and antidepressant effects in mice.

We investigated the effects of histamine and GABA A receptor agents on pain and depression-like behaviors and their interaction using a tail-flick test and the forced swimming test (FST) in male mice. Our data revealed that intraperitoneal administration of muscimol (0.12 and 0.25 mg/kg) increased the percentage of maximum possible effect (%MPE) and area under the curve (AUC) of %MPE, indicating an antinociceptive response. Intraperitoneal injection of bicuculline (0.5 and 1 mg/kg) decreased %MPE and AUC of %MPE, suggesting hyperalgesia. Moreover, muscimol by reducing the immobility time of the FST elicited an antidepressant-like response but bicuculline by enhancing the immobility time of the FST caused a depressant-like response. Intracerebroventricular (i.c.v.) microinjection of histamine (5 µg/mouse) enhanced %MPE and AUC of %MPE. i.c.v. infusion of histamine (2.5 and 5 µg/mouse) decreased immobility time in the FST. Co-administration of different doses of histamine along with a sub-threshold dose of muscimol potentiated antinociceptive and antidepressant-like responses produced by histamine. Cotreatment of different doses of histamine plus a noneffective dose of bicuculline reversed antinociception and antidepressant-like effects elicited by histamine. Cotreatment of histamine, muscimol, and bicuculline reversed antinociceptive and antidepressant-like behaviors induced by the drugs. The results demonstrated additive antinociceptive and antidepressant-like effects between histamine and muscimol in mice. In conclusion, our results indicated an interaction between the histaminergic and GABAergic systems in the modulation of pain and depression-like behaviors.

Renal histaminergic system and acute effects of histamine receptor 2 blockade on renal damage in the Dahl salt-sensitive rat.

Histamine is involved in the regulation of immune response, vasodilation, neurotransmission, and gastric acid secretion. Although elevated histamine levels and increased expression of histamine metabolizing enzymes have been reported in renal disease, there is a gap in knowledge regarding the mechanisms of histamine-related pathways in the kidney. We report here that all four histamine receptors as well as enzymes responsible for the metabolism of histamine are expressed in human and rat kidney tissues. In this study, we hypothesized that the histaminergic system plays a role in salt-induced kidney damage in the Dahl salt-sensitive (DSS) rat, a model characterized with inflammation-driven renal lesions. To induce renal damage related to salt sensitivity, DSS rats were challenged with 21 days of a high-salt diet (4% NaCl); normal-salt diet (0.4% NaCl)-fed rats were used as a control. We observed lower histamine decarboxylase and higher histamine N-methyltransferase levels in high-salt diet-fed rats, indicative of a shift in histaminergic tone; metabolomics showed higher histamine and histidine levels in the kidneys of high-salt diet-fed rats, whereas plasma levels for both compounds were lower. Acute systemic inhibition of histamine receptor 2 in the DSS rat revealed that it lowered vasopressin receptor 2 in the kidney. In summary, we established here the existence of the local histaminergic system, revealed a shift in the renal histamine balance during salt-induced kidney damage, and provided evidence that blockage of histamine receptor 2 in the DSS rat affects water balance and urine concentrating mechanisms.NEW & NOTEWORTHY Histamine is a nitrogenous compound crucial for the inflammatory response. The knowledge regarding the renal effects of histamine is very limited. We showed that renal epithelia exhibit expression of the components of the histaminergic system. Furthermore, we revealed that there was a shift in the histaminergic tone in salt-sensitive rats when they were challenged with a high-salt diet. These data support the notion that histamine plays a role in renal epithelial physiological and pathophysiological functions.