piperidines and imetit

Myocardial infarction is an alarming health issue, needs great attention. The present study investigated the role of histamine-H3 receptor (H3R) agonist imetit in relationship to sympathetic and renin angiotensin system in Wistar rats.. Subcutaneous injection of isoproterenol (85 mg/kg) on last 2 consecutive days in per se group and 7 days treatment of different groups at 24 h interval induced myocardial infarction in Wistar rats. H3R agonist imetit (10 mg/kg), H3R antagonist thioperamide (5 mg/kg), losartan (10 mg/kg) were administered orally to evaluate imetit's cardioprotective potential effect by measuring plasma cardiac antioxidant markers, angiotensin II, norepinephrine levels and histopathological analysis.. Isoproterenol significantly elevated the angiotensin II and norepinephrine levels in rat plasma. This study revealed that pre-treatment with imetit similar to losartan attenuated norepinephrine and angiotensin II levels whereas thioperamide showed its antagonistic effect by diminishing imetit's effects. Furthermore, its protective effect was confirmed by restoration of cardiac antioxidant markers and histopathological improvement of myocardium integrity.. This study confirm imetit's cardioprotective potential and also reveals renin angiotensin system, sympathetic system and H3R correlation in isoproterenol induced toxicity in rats. However, molecular studies must be warranted to prove the role of H3R in myocardial infarction.

Topics: Angiotensin II; Animals; Antioxidants; Cardiotonic Agents; Histamine Agonists; Histamine H3 Antagonists; Imidazoles; Isoproterenol; Losartan; Male; Myocardial Infarction; Myocardium; Norepinephrine; Piperidines; Rats; Renin-Angiotensin System; Sympathetic Nervous System; Thiourea

Recently we reported that cultured rat cortical astrocytes express histamine H3 receptor that is functionally coupled to Gi/o proteins and participates to the stimulatory effect of histamine. Due to the lack of data on the distribution of histamine H3 receptors on glial cells we further investigated their presence in cultured astrocytes from different brain regions. Real-time PCR was performed to examine the expression of native histamine H3 receptor in cultured rat astrocytes from cortex,cerebellum, hippocampus and striatum.Double-antigen immunofluorescence staining and[3H]N-α-methylhistamine([3H]NαMH) binding studies were utilized to specifically identify and characterize receptor binding sites in astrocytes. Histamine H3 receptor mRNA was detected in rat astrocytes from all the regions under investigation with the highest levels in striatal astrocytes followed by hippocampal astrocytes and approximately equal levels in cerebellar and cortical astrocytes.Double-antigen immunofluorescence confirmed the presence of histamine H3 receptors on the membrane of all examined astroglial populations.[3H]NαMH bound with high affinity and specificity to an apparently single class of saturable sites on cortical astrocytic membranes(KD¼4.5570.46 nM; Bmax¼5.6370.21 fmol/mg protein)and competition assays with selective agonists and antagonists were consistent with labeling of histamine H3 receptor(range of pKi values 7.50–8.87). Our study confirmed the ability of cultured astrocytes from different rat brain regions to express histamine H3 receptors.The observed diverse distribution of the receptors within various astrocytic populations possibly mirrors their heterogeneity in the brain and indicates their active involvement in histamine-mediated effects.

Topics: Animals; Animals, Newborn; Astrocytes; Binding, Competitive; Brain; Cells, Cultured; Ciprofloxacin; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Methylhistamines; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; RNA, Messenger; Thiourea

Recent studies suggest that the brain histaminergic system and especially the H3 receptors are involved in the regulation of alcohol consumption and alcohol-induced behaviors. Part of this effect might be due to a modulation of ethanol-induced sedation by central histamine. The aim of the present study was to investigate the effects of several histaminergic drugs on ethanol-induced sedation using the loss of righting reflex experimental protocol in female Swiss mice. A pretreatment with L-histidine, the histamine precursor, significantly reduced ethanol-induced sedation, suggesting that brain histamine protects against the sedative effects of ethanol. In a second set of experiments, several H3 receptor agonists (immepip or imetit) and inverse agonists/antagonists (thioperamide, A331440, or BF2.649) were tested. Surprisingly, both H3 receptor agonists and antagonists potentiated the sedative effects of ethanol. This paradoxical effect might be due to the subtle regulatory actions related to the H3 heteroreceptor function.

Topics: Animals; Biphenyl Compounds; Brain; Ethanol; Female; Histidine; Hypnotics and Sedatives; Imidazoles; Mice; Nitriles; Piperidines; Pyrrolidines; Receptors, Histamine H3; Reflex, Righting; Thiourea

Centrally acting histamine H(3) receptor ligands are proposed as potential treatments for obesity, although the value of inverse agonists at these receptors is still debated. Functional inhibition of H(3) autoreceptors activates neurones in a hypothalamic 'satiety' centre. The H(3) receptor antagonist, proxyfan was used as a tool to assess the action of histaminergic compounds in this model.. We compared the actions of histamine on feeding with those of an H(3) receptor agonist (imetit) and inverse agonist (thioperamide) in rats and mice. Sites of action were identified by immunohistochemistry and the hypothalamic ventromedial nucleus (VMN) was investigated using electrophysiological techniques.. Central histamine or thioperamide decreased fast-induced feeding, whereas imetit increased feeding. Systemic thioperamide entered the brain to activate hypothalamic feeding centres and to reduce feeding without causing any adverse behaviours. Thioperamide activated neurones in the VMN through an action on histamine autoreceptors, whilst imetit had the opposite effect. Proxyfan administered alone did not affect either feeding or electrical activity. However, it blocked the actions of both thioperamide and imetit, acting as a neutral antagonist in this system.. The H(3) receptor inverse agonist, thioperamide, potently reduced appetite without adverse behavioural effects. This action was blocked by proxyfan, acting as a neutral antagonist in this model and, therefore, this compound is useful in determining the selectivity of H(3) receptor-directed drugs. A major action of thioperamide is through presynaptic autoreceptors, inducing stimulation by endogenous histamine of postsynaptic H(1 ) receptors on anorectic hypothalamic neurones.

Topics: Animals; Eating; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Mice; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Thiourea; Ventromedial Hypothalamic Nucleus

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.

Topics: Animals; Behavior, Animal; Central Nervous System Stimulants; Histamine; Histamine Agonists; Hypothalamus; Imidazoles; Male; Methamphetamine; Methylhistamines; Mice; Motor Activity; Piperidines; Random Allocation; Stereotyped Behavior; Thiourea

Siberian hamsters develop hypophagia and increase catabolism of fat reserves in response to short photoperiods resulting in a natural loss of body weight in winter. We previously found that histamine 3 receptor (H3R) mRNA in the posterior hypothalamus is significantly decreased in short photoperiods. We hypothesized that this lower expression of H3R might contribute to the winter hypophagic state, therefore we examined the effects of the H3R agonist imetit and inverse agonists clobenpropit and thioperamide on food intake. We expressed the Siberian hamster H3R receptor in vitro and confirmed that imetit, clobenpropit and thioperamide are bound specifically, thus validating them as tools to investigate the role of H3R in vivo. Intracerebroventricular administration of histamine decreased food intake in hamsters in the fat summer state. Administration of imetit to hamsters in the lean state increased food intake, whereas administration of inverse agonists decreased food intake, though this was associated with decreased locomotor activity. Both H3R inverse agonists prevented the nocturnal rise in body temperature indicating additional effects on energy expenditure. In summary, our results suggest that increased availability of central histamine or the reduction of H3R activity decrease food intake. These effects are similar to those observed in hamsters in short photoperiods.

Topics: Animals; Body Temperature; Cell Line, Transformed; Cricetinae; Disease Models, Animal; Eating; Histamine; Imidazoles; Injections, Intraventricular; Motor Activity; Obesity; Phodopus; Photoperiod; Piperidines; Receptors, Histamine H3; Seasons; Thiourea; Transfection

Histamine 3 (H(3)) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H(3) receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H(3) receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.

Topics: Acetylcholine; Animals; Anticonvulsants; Brain; Cholinesterase Inhibitors; Cognition; Conditioning, Operant; Donepezil; Drinking Behavior; Drug Evaluation, Preclinical; Histamine Agonists; Histamine Antagonists; Imidazoles; Indans; Learning; Microdialysis; Morpholines; Muscarinic Antagonists; Nootropic Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Scopolamine; Synaptic Transmission; Thiourea

Despite the well-established role of histamine as an anorexigenic neurotransmitter, the role of histamine H(3) receptors in feeding behavior is controversial. Herein we investigated the role of histamine H(3) receptor on several orexigenic agents in mice. Thioperamide (histamine H(3) receptor inverse agonist) inhibited neuropeptide Y- and nociceptin-induced hyperphagia but had no effect on U-50488 (opioid kappa-receptor agonist)-induced hyperphagia. In contrast, imetit (histamine H(3) receptor agonist) inhibited U-50488-induced hyperphagia but augmented neuropeptide Y-induced hyperphagia while it did not alter nociceptin-induced hyperphagia. These results indicate distinctive roles of histamine H(3) receptors in various orexigenic pathways.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Appetite; Histamine Agonists; Histamine H3 Antagonists; Hyperphagia; Imidazoles; Male; Mice; Mice, Inbred C57BL; Neuropeptide Y; Nociceptin; Opioid Peptides; Piperidines; Receptors, Histamine H3; Thiourea

Histamine H3 receptors (H3Rs) are located on the presynaptic membranes and cell soma of histamine neurons, where they negatively regulate the synthesis and release of histamine. In addition, H3Rs are also located on nonhistaminergic neurons, acting as heteroreceptors to regulate the releases of other amines such as dopamine, serotonin, and norepinephrine. The present study investigated the effects of H3R ligands on appetite and body-weight regulation by using WT and H3R-deficient mice (H3RKO), because brain histamine plays a pivotal role in energy homeostasis. The results showed that thioperamide, an H3R inverse agonist, increases, whereas imetit, an H3R agonist, decreases appetite and body weight in diet-induced obese (DiO) WT mice. Moreover, in DiO WT mice, but not in DiO H3RKO mice, imetit reduced fat mass, plasma concentrations of leptin and insulin, and hepatic triglyceride content. The anorexigenic effects of imetit were associated with a reduction in histamine release, but a comparable reduction in histamine release with alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, increased appetite. Moreover, the anorexigenic effects of imetit were independent of the melanocortin system, because imetit comparably reduced appetite in melanocortin 3 and 4 receptor-deficient mice. The results provide roles of H3Rs in energy homeostasis and suggest a therapeutic potential for H3R agonists in the treatment of obesity and diabetes mellitus.

Topics: Animals; Appetite; Body Weight; Diabetes Mellitus; Histamine Agonists; Imidazoles; Insulin; Leptin; Mice; Mice, Knockout; Obesity; Piperidines; Receptors, Histamine H3; Thiourea

In rats lesioned neonatally with 6-hydroxydopamine (6-OHDA), repeated treatment with SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol), a dopamine D(1)/D(5) receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D(1) receptor supersensitivity is known as a priming phenomenon, and this process is thought to underlie not only the appearance of vacuous chewing movements in humans with tardive dyskinesia, but also the onset of motor dyskinesias in L-dihydroxyphenylalanine (L-DOPA)-treated Parkinson's disease patients. The object of the present study was to determine the possible influence of the histaminergic system on dopamine D(1) agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H(3) receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H(3) receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D(1) agonist-primed rats, thioperamide alone produced a vacuous chewing movements response (i.e., P < 0.05 vs SKF 38393, 1.0 mg/kg i.p.), but did not modify the SKF 38393 effect. Notably, both imetit and thioperamide-induced catalepsy in both non-primed and primed 6-OHDA-lesioned rats, comparable in magnitude to the effect of the dopamine D(1)/D(5) receptor antagonist SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.5 mg/kg i.p.). Furthermore, in primed animals both imetit and thioperamide intensified SCH 23390-evoked catalepsy. In vivo microdialysis established that neither imetit nor thioperamide altered extraneuronal levels of dopamine and its metabolites in the striatum of 6-OHDA-lesioned rats. On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Animals, Newborn; Benzazepines; Catalepsy; Corpus Striatum; Dialysis Solutions; Dopamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Mastication; Microdialysis; Motor Activity; Oxidopamine; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Stereotyped Behavior; Thiourea

The existence of mouse H3-receptor isoforms was investigated by PCR analysis and cDNA cloning. Splicing mechanisms previously reported in various species are conserved in the mouse. The retention/deletion of a fragment in the third intracellular loop of the mouse receptor leads to the existence of three isoforms designated mH(3(445)), mH(3(413)) and mH(3(397)) according to the length of their deduced amino acid sequence. PCR analysis showed that mouse H3-receptor isoforms display different expression patterns in the brain. Following expression in Cos-1 cells, [125I]iodoproxyfan binding indicated similar pharmacological profiles of the mH(3(445)), mH(3(413)) and mH(3(397)) isoforms. The pharmacological profile of the mouse H3 receptor is more similar to the rat receptor than to the human receptor, although some differences were also observed between the mouse and rat receptors. For example, the potency of thioperamide and ciproxifan is slightly higher at the mouse receptor than at the rat receptor but 40-100-fold higher than at the human receptor. In situ hybridization histochemistry showed that the distribution of H3-receptor mRNAs in the mouse brain is rather similar to that previously reported in the rat brain. However, the autoradiographic and cellular expression patterns observed in several brain areas such as the thalamus or hippocampus reveal important differences between the two species.

Topics: Animals; Blotting, Northern; Brain; Chlorocebus aethiops; Cloning, Molecular; Competitive Bidding; COS Cells; Gene Expression; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; In Situ Hybridization; Iodine Radioisotopes; Isoenzymes; Mice; Piperidines; Radioligand Assay; Rats; Receptors, Histamine H3; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thiourea; Transfection

Despite histamine being a potent endogenous vasoactive agent released in increasing amounts postburn, its role in postburn oedema formation has been controversial and its effect on burn circulation poorly investigated. The present study investigated the involvement of H(1), H(2) and H(3) receptors in postburn edema in rats exposed to skin and muscle burns and their influence on skin circulation postburn. We used the selective antagonists clemastine (H(1)), ranitidine (H(2)), thioperamide (H(3)) and the selective H(3) receptor agonist, imetit. Results showed that none of the antagonists or the H(3) agonist had significant effect on postburn edema measured by quantitative spectrophotometric analysis of extravasated Evans blue-albumin in the full-thickness burned skin or muscle. Clemastine and thioperamide failed to induce significant effect on blood flow in the partial- or full-thickness skin burn injury as measured by laser Doppler flowmetry, while ranitidine significantly (P<0.01) reduced blood flow in the full-thickness burn. In contrast, the H(3) receptor agonist, imetit, significantly increased blood flow, both in the partial-thickness burn injury (P<0.05) and in the full-thickness burn (P<0.01). Moreover, imetit significantly (P<0.01) increased mean arterial pressure while thioperamide significantly (P<0.01) reduced systemic pressure. In conclusion, H(1), H(2) and H(3) receptors are not important actors in the regulation of vascular patency permeability, whereas H(3) receptors play an important role by increasing skin circulation postburn, presumably by relaxation of vascular smooth muscle and/or by interacting with other inflammatory neurotransmitters. Data also suggest that H(2) receptor blockers may not be best choice for stress ulcer prophylaxis in burn patients.

Topics: Animals; Burns; Clemastine; Edema; Histamine Agonists; Histamine H1 Antagonists; Histamine H2 Antagonists; Imidazoles; Male; Piperidines; Ranitidine; Rats; Rats, Sprague-Dawley; Receptors, Histamine; Receptors, Histamine H3; Regional Blood Flow; Skin; Statistics, Nonparametric; Thiourea

Histamine H3 receptors modulate histamine synthesis, although little is known about the transduction mechanisms involved. To investigate this issue, we have used a preparation of rat brain cortical miniprisms in which histamine synthesis can be modulated by depolarization and by H3 receptor ligands. When the miniprisms were incubated in presence of forskolin, dibutyryl-cAMP, or 3-isobutyl-1-methylxanthine (IBMX), histamine synthesis was stimulated in 34, 29, and 47%, respectively. These stimulations could be prevented by the selective cAMP protein kinase blocker Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPs). Preincubation with the H3 receptor agonist imetit prevented IBMX- (100% blockade) and forskolin- (70% blockade) induced stimulation of histamine synthesis. The H3 inverse agonist thioperamide enhanced histamine synthesis in the presence of 1 mM IBMX or 30 mM potassium (+47 and +45%, respectively). Similarly, the H3 antagonist clobenpropit enhanced histamine synthesis in the presence of 30 mM potassium (+ 59%). The cAMP-dependent protein kinase blockers Rp-cAMPs and PKI14-22 could impair the effects of thioperamide and clobenpropit, respectively. These results indicate that the adenylate cyclase-protein kinase A pathway is involved in the modulation of histamine synthesis by H3 autoreceptors present in histaminergic nerve terminals.

Topics: 1-Methyl-3-isobutylxanthine; Animals; Brain; Bucladesine; Colforsin; Cyclic AMP; Drug Interactions; Histamine; Imidazoles; In Vitro Techniques; Male; Piperidines; Potassium; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3; Thionucleotides; Thiourea

Following a previous report by our research group on discriminative properties of a series of aliphatic histamine homologues, we now studied immepip, imetit and its lower and higher sidechain homologues as ligands for the histamine H(3) receptor in a [(125)I]-iodophenpropit binding assay using rat cerebral cortex membranes, and two functional H(3) receptor models (inhibition of the neurogenic contraction of the guinea pig jejunum and inhibition of [(3)H]-noradrenaline release in rat cerebral cortex slices). The immepip homologues behaved as competitive H(3)-receptor antagonists in both functional systems. The potencies (pA(2) values) observed at the guinea pig jejunum were 8.4 and 6.2 for the immepip homologues VUF 4929 and VUF 4735, respectively, whereas on the electrically evoked release of [(3)H]-noradrenaline from cortical slices the pA(2) values were 7.1 and 5.5 for VUF 4929 and VUF 4735, respectively. Moreover, immepip, but not the (R)-alpha-methylhistamine, showed almost a tenfold higher agonistic potency in the rat cerebral cortex than in the guinea pig jejunum. For imetit and its homologues important discrepancies in the potencies in the two functional assays were noticed as well. VUF 8328 acts as a potent (pD(2)=8.0) partial agonist in the brain, but as a very active (pA(2)=9.4) competitive antagonist in the guinea pig jejunum. The partial agonistic activity of VUF 8328 in the brain was confirmed by GTP gamma S-sensitive, biphasic displacement of [(125)I]-iodophenpropit binding to rat cerebral cortex membranes. The differences in potencies shown by the various ligands are discussed in relation to H(3) receptor heterogeneity.

Topics: Animals; Cerebral Cortex; Guinea Pigs; Histamine Agonists; Imidazoles; Jejunum; Male; Piperidines; Radioligand Assay; Rats; Receptors, Histamine H3; Structure-Activity Relationship; Thiourea

We studied the effects of histamine H(3) receptor ligands on the release of endogenous acetylcholine from the isolated, vascularly perfused rat stomach. The stomach was perfused via the celiac artery with modified Krebs-Ringer solution containing physostigmine. Released acetylcholine from the portal vein was electrochemically measured using high-performance liquid chromatography and an enzyme system. Vagus nerves were electrically stimulated twice for 2 min (0.5 or 2.5 Hz). Acetylcholine release evoked at 2.5 Hz was slightly inhibited by histamine and effectively potentiated by thioperamide, a histamine H(3) receptor antagonist. Acetylcholine release evoked at 0.5 Hz in the presence of atropine was not influenced by thioperamide, but effectively inhibited by histamine, R-alpha-methylhistamine or imetit, histamine H(3) receptor agonists. These inhibitory effects were abolished by thioperamide or pertussis toxin. These results suggest that histamine attenuates acetylcholine release from vagus nerves through histamine H(3) receptor-mediated and pertussis toxin-sensitive mechanisms in the rat stomach.

Topics: Acetylcholine; Animals; Atropine; Gastric Mucosa; GTP-Binding Proteins; Histamine; Imidazoles; Male; Methylhistamines; Perfusion; Pertussis Toxin; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea; Vagus Nerve; Virulence Factors, Bordetella

The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.

Topics: Animals; Apomorphine; Chlorpheniramine; Dimaprit; Diphenhydramine; Dopamine Agonists; Drug Interactions; Famotidine; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Piperidines; Ranitidine; Rats; Rats, Sprague-Dawley; Stereotyped Behavior; Thiourea; Toluidines

Stimulation-evoked 3H-noradrenaline release in human cerebrocortical slices was inhibited by histamine (in a manner sensitive to clobenpropit) and by imetit, suggesting H3 receptor-mediated inhibition of noradrenaline release in human brain.

Topics: Animals; Brain; Cerebral Cortex; Dimethindene; Electric Stimulation; Hippocampus; Histamine; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; Male; Mice; Mice, Inbred Strains; Norepinephrine; Piperidines; Ranitidine; Receptors, Histamine H3; Thiourea; Tritium

In previous research we found that pre-training administration of histamine H3 receptor agonists such as (R)-alpha-methylhistamine and imetit impaired rat performance in object recognition and a passive avoidance response at the same doses at which they inhibited the release of cortical acetylcholine in vivo. Conversely, in the present study we report that the post-training administration of (R)-alpha-methylhistamine and imetit failed to affect rat performance in object recognition and a passive avoidance response, suggesting that H3 receptor influences the acquisition and not the recall processes. We also investigated the effects of two H3 receptor antagonists, thioperamide and clobenpropit, in the same behavioral tasks. Pre-training administration of thioperamide and clobenpropit failed to exhibit any procognitive effects in normal animals but prevented scopolamine-induced amnesia. However, also post-training administration of thioperamide prevented scopolamine-induced amnesia. Hence, the ameliorating effects of scopolamine-induced amnesia by H3 receptor antagonism are not only mediated by relieving the inhibitory action of cortical H3 receptors, but other mechanisms are also involved. Nevertheless, H3 receptor antagonists may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.

Topics: Amnesia; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Cognition; Histamine Agonists; Histamine Antagonists; Imidazoles; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Methylhistamines; Pattern Recognition, Visual; Piperidines; Rats; Rats, Wistar; Receptors, Histamine H3; Scopolamine; Thiourea

The ability of histamine H3 receptor ligands to interact with 5-HT3 receptors in NG108-15 cells was studied using the whole cell patch clamp recording technique. Imetit, a histamine H3 receptor agonist, generated inward currents and exhibited weak partial agonist activity at the 5-HT3 receptor (EC50 = 11.8 microM). Imetit-induced currents were slow to desensitize and at a high concentration reduced in size. The histamine H3 receptor antagonists iodophenpropit and thioperamide did not generate inward currents but were able to inhibit 5-hydroxytryptamine (5-HT) responses with an IC50 of 1.57+/-0.3 microM and 13.7+/-3.5 microM, respectively. Thioperamide is probably a non-competitive antagonist which may have more than one binding site on the receptor.

Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Histamine Agonists; Histamine Antagonists; Hybrid Cells; Imidazoles; Ion Channels; Isothiuronium; Membrane Potentials; Mice; Piperidines; Rats; Receptors, Histamine H3; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists; Thiourea

We compared the effects of modulating the postsynaptic histamine receptor subtype 2 (H2) and inhibitory presynaptic autoreceptor subtype 3 (H3) on memory processing in the septum. Mice were partially trained on footshock avoidance in a T-maze. Immediately after training, saline or a drug solution was infused into the septum. One week later, retention was tested by continuing training until the mice made five avoidance responses in six consecutive trials. The results indicate that dimaprit, an H2 agonist, facilitated retention (25 and 50 pg) with a U-shaped dose-response curve typical of drugs acting at postsynaptic receptors. Cimetidine, an H2 antagonist, impaired retention (15-50 ng). The H3 agonist. imetit, impaired retention (25-200 ng), while the H3 antagonist, thioperamide, facilitated retention (10-400 ng). An unusual feature of the dose-response curve for thioperamide was that it did not appeal to yield a U-shaped curve as occurs with drugs acting postsynaptically, but facilitated retention to approximately the same degree from 50 to 400 ng. As histamine neurons project to various limbic system structures involved in memory processing, it may play an important role in regulating the activity of structures such as the septum, hippocampus and amygdala.

Topics: Animals; Cimetidine; Dimaprit; Histamine Agonists; Histamine Antagonists; Imidazoles; Limbic System; Male; Memory; Mice; Piperidines; Thiourea

Our previous results demonstrate the occurrence of presynaptic inhibitory histamine H3 receptors on sympathetic neurons innervating resistance vessels of the pithed rat. The present study, in which new H3 receptor ligands with increased potency and selectivity (imetit, clobenpropit) were used, was designed to further explore the role of H3 receptors in the regulation of the rat cardiovascular system. In particular we were interested whether these receptors may be activated by endogenous histamine and whether they are detectable in an experimental model of hypertension. All experiments were performed on pithed and vagotomized rats treated with rauwolscine 1 mumol/kg. In normotensive Wistar rats the electrical (1 Hz, 1 ms, 50 V for 20 s) stimulation of the preganglionic sympathetic nerve fibres increased diastolic blood pressure by about 35 mmHg. Two H3 receptor agonists, R-(-)-alpha-methylhistamine and imetit, inhibited the electrically induced increase in diastolic blood pressure in a dose-dependent manner. The maximal effect (about 25%) was obtained for R-(-)-alpha-methylhistamine at about 10 mumol/kg and for imetit at about 1 mumol/kg. Two H3 receptor antagonists, thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg, attenuated the inhibitory effect of imetit. The neurogenic vasopressor response was increased by about 15% by thioperamide 1 mumol/kg and clobenpropit 0.1 mumol/kg and decreased by 25% by the histamine methyltransferase inhibitor metoprine 37 mumol/kg. R-(-)-alpha-Methylhistamine, imetit, thioperamide, clobenpropit and metoprine did not affect the vasopressor response to exogenously added noradrenaline 0.01 mumol/kg (which increased diastolic blood pressure by about 40 mmHg). Metoprine had only a very low affinity for H3 binding sites (labelled by 3H-N alpha-methylhistamine; pKi 4.46). In pithed Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats, electrical (1 Hz, 1 ms, 50 V for 10 s) stimulation increased diastolic blood pressure by 28 and 37 mmHg, respectively. Imetit inhibited the neurogenic vasopressor response to about the same extent in WKY and SHR rats (maximal effect of about 30%). The inhibitory influence of imetit was diminished by thioperamide 1 mumol/kg to about the same degree in rats of either strain. The present study confirms the occurrence of presynaptic H3 receptors on sympathetic nerve fibres involved in the inhibition of the neurogenic vasopressor response. Moreover, it demonstrates that these H3 receptors are

Topics: Adrenergic Fibers; Animals; Blood Pressure; Decerebrate State; Electric Stimulation; Histamine; Histamine Agonists; Histamine Antagonists; Hypertension; Imidazoles; Male; Methylhistamines; Piperidines; Pyrimethamine; Rats; Rats, Wistar; Receptors, Histamine H3; Thiourea; Vagotomy; Vascular Resistance

We examined the possible existence of prejunctional histamine H3 receptors on sympathetic nerve fibers innervating rat tail artery. The stimulation-evoked tritium outflow from isolated vessels preincubated with [3H]-noradrenaline and perfused/superfused in the presence of the alpha2-adrenoceptor antagonist rauwolscine, 3 microM, was inhibited by histamine 10 microM (by 8%) and the H3 agonists R-(-)-alpha-methylhistamine, 10 microM (by 18%), and imetit, 0.1-10 microM (by < or =20%). The inhibitory effect of imetit, which did not occur in the absence of rauwolscine, was counteracted by thioperamide, 1 microM. In the presence of rauwolscine, 3 microM, the inhibitory effect of imetit also occurred when the current strength or the Ca2+ concentration in the medium was reduced to compensate for the increase in tritium overflow elicited by rauwolscine, indicating that the inhibitory action of imetit is not associated with the increase in noradrenaline release produced by rauwolscine. In spontaneously hypertensive rats (SHRs), imetit also inhibited the overflow of tritium. This inhibitory effect was comparable to that observed in Wistar-Kyoto (WKY) rats and indicates that the sympathetic nerves of the rat tail artery in SHRs, like those in normotensive rats, are endowed with prejunctional histamine H3 receptors.

Topics: Adrenergic alpha-2 Receptor Antagonists; Animals; Arteries; Electric Stimulation; Histamine; Histamine Agonists; Imidazoles; Male; Norepinephrine; Piperidines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Histamine H3; Sympathetic Fibers, Postganglionic; Thiourea; Yohimbine

The modulatory role of histamine H3 receptors in pulmonary oedema induced by acetylcholine, capsaicin and by exogenous substance P was investigated in isolated, ventilated rabbit lungs. Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c). Acetylcholine (10(-8) to 10(-4) M), substance P (10(-10) to 10(-6) M), capsaicin (10(-4) M) and 5-hydroxytryptamine (5-HT) (10(-4) M) induced an increase in the Kf,c. Carboperamide, a novel histamine H3 receptor antagonist, induced a significant leftward shift of the concentration-response curve to acetylcholine and also enhanced the effect of capsaicin on the Kf,c, while it had no significant effect on the response to substance P and 5-HT. Imetit, a new histamine H3 receptor agonist, strongly inhibited the effects of acetylcholine and capsaicin. Imetit also strongly protected the lung against substance P effects but did not prevent the 5-HT-induced increase in the Kf,c. Carboperamide completely blocked the inhibitory effect of Imetit on the acetylcholine response. (R)-alpha-Methylhistamine, an other histamine H3 receptor agonist, had the same protective effect against acetylcholine response as Imetit. We conclude that histamine H3 receptors could protect the lung against acetylcholine- and capsaicin-induced oedema via a prejunctional modulatory effect on the C-fibres. However, since the response to exogenous substance P was also inhibited by histamine H3 receptor stimulation, the presence of such receptors at a postsynaptic level, probably on mast cells, was also suggested.

Topics: Acetylcholine; Animals; Capillary Permeability; Capsaicin; Dose-Response Relationship, Drug; Drug Interactions; Endothelium; Female; Histamine Agonists; Histamine Antagonists; Imidazoles; In Vitro Techniques; Lung; Male; Nerve Fibers; Piperidines; Pulmonary Edema; Rabbits; Receptors, Histamine H3; Serotonin; Substance P; Thiourea

Norepinephrine release contributes to ischemic cardiac dysfunction and arrhythmias. Because activation of histamine H3-receptors inhibits norepinephrine release, we searched for the presence of H3-receptors directly in sympathetic nerve endings (cardiac synaptosomes) isolated from surgical specimens of human atria. Norepinephrine was released by depolarization with K+. The presence of H3-receptors was ascertained because the selective H3-receptor agonists (R) alpha-methylhistamine and imetit reduced norepinephrine release, and the specific H3-receptor antagonist thioperamide blocked this effect. Norepinephrine release was exocytotic, since it was inhibited by the N-type Ca(2+)-channel blocker omega-conotoxin and the protein kinase C inhibitor Ro31-8220. Functional relevance of these H3-receptors was obtained by showing that transmural electrical stimulation of sympathetic nerve endings in human atrial tissue increased contractility, an effect blocked by propranolol and attenuated in a concentration-dependent manner by (R) alpha-methylhistamine. Also, thioperamide antagonized the effect of (R) alpha-methylhistamine. Our findings are the first demonstration that H3-receptors are present in sympathetic nerve endings in the human heart, where they modulate adrenergic responses by inhibiting norepinephrine release. Since myocardial ischemia causes intracardiac histamine release, H3-receptor-induced attenuation of sympathetic neurotransmission may be clinically relevant.

Topics: Cell Separation; Electric Stimulation; Exocytosis; Heart; Histamine Agonists; Histamine Antagonists; Humans; Imidazoles; In Vitro Techniques; Indoles; Methylhistamines; Myocardial Ischemia; Myocardium; Norepinephrine; Piperidines; Protein Kinase C; Receptors, Histamine H3; Synaptosomes; Thiourea

Bombesin (BN) and its mammalian homologue, gastrin-releasing peptide (GRP), are potent satiety agents and have been implicated in the physiological regulation of food intake. The mechanism(s) of action of this effect remains unclear. There is a functional and anatomic overlap between histamine and BN in relationship to feeding, which led us to hypothesize that BN may mediate its satiety effects through activation of the histaminergic system. To assess this contention, we examined the effects of R-alpha-methylhistamine (alpha-MH) and Imetit, selective H3-receptor agonists that inhibit the release and synthesis of histamine, on BN- or cholecystokinin (CCK)-induced satiety. In this report we present the first evidence for the role of histamine H3 receptors in the mediation of BN-elicited satiety. During the first hour of the 4-h daily feeding session, BN reduced food intake by > 50% relative to the control condition; this suppression was blocked by prior treatment with the H3-receptor agonist, alpha-MH. This blockade of BN-induced satiety was dose related and selective to BN as alpha-MH failed to attenuate sulfated CCK-8-induced satiety. When alpha-MH was administered alone, it failed to significantly affect food intake. The specificity of this effect was further supported by the demonstration that another H3 agonist, Imetit, was also able to block the feeding-suppressant effects of BN. Furthermore, thioperamide, an H3-receptor antagonist, blocked these effects of Imetit.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Behavior, Animal; Bombesin; Eating; Gastrin-Releasing Peptide; Histamine; Histamine Agonists; Histamine Antagonists; Imidazoles; Male; Methylhistamines; Motor Activity; Peptides; Piperidines; Rats; Rats, Sprague-Dawley; Satiation; Sincalide; Thiourea