H3 Receptor Agonist Research Articles

Histamine H3 receptor antagonists display antischizophrenic activities in rats treated with MK-801.

Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p.) on MK-801 (0.2 mg/kg, i.p.)-induced locomotor activity and also measured dopamine and histamine levels in rat's brain homogenates. The study also included clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively. Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal locomotor activity, which was reduced with CPX and CBP. MK-801-induced locomotor hyperactivity attenuated by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised striatal dopamine level, which was reduced in rats pretreated with CPX and CBP. CPZ also significantly lowered striatal dopamine levels, although the decrease was less robust compared to CLZ, CPX, and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.), counteracted the effect of CPX and CBP. The present study shows the positive effects of CPX and CBP on MK-801-induced schizophrenia-like behaviors in rodents.

Effect of histamine receptors agonists or antagonists administered intracerebroventricularly and intrathecally on the blood glucose level in immobilization stress model

Effects of histamine receptors agonists or antagonists administered centrally (supraspinally or spinally) on immobilization stress-induced blood glucose levels were studied in Institute for Cancer Research mice. Mice were pretreated intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with histamine (H1, H2, H3 and H4) receptor agonists or antagonists 10 min prior to immobilization stress (IMO) stimulation for 30 min. We found that the increased blood glucose level induced by IMO was attenuated by the i.c.v. pretreatment with α-methylhistamine (H3 agonist). However, H3 antagonist, H1, H2 and H4 receptor agonists and antagonists did not affect the blood glucose level. Also, i.t. pretreatment with α-methylhistamine or VUF 8430 attenuated the increased blood glucose level induced by IMO. In addition, cetirizine and carcinine enhanced the increased blood glucose level induced by IMO. However, the blood glucose level was not affected by H1 and H2 receptor agonists, H2 and H4 receptor antagonists. Corticosterone and insulin levels were also measured in α-methylhistamine (i.c.v or i.t) and with VUF 8430, carcinine and cetirizine (i.t.) treated group. We found that the corticosterone level was increased only by i.t treatment with α-methylhistamine, whereas the insulin level was attenuated by i.c.v or i.t. treatment with α-methylhistamine and i.t treatment with VUF 8430, carcinine and cetirizine. Our results suggest the active involvement of histamine receptor in blood glucose regulation in IMO.

Morphine modulates the effects of histamine H1 and H3 receptors on seizure susceptibility in pentylenetetrazole-induced seizure model of mice

Histamine regulates release of neurotransmitters such as dopamine, serotonin, gamma-aminobutyric acid (GABA), glutamate and also is involved in several functions in central nervous system (CNS). It has been shown that histamine participates in disorders like seizure. It has been well documented that morphine dose-dependently induces anti or proconvulsant effects. In the current study, we firstly showed that morphine (1mg/kg) exerts anticonvulsant effects which significantly reversed by naltrexone administration. Secondly, we determined seizure threshold for H1 and H3 receptors agonists and antagonists in mouse model of pentylenetetrazole (PTZ)-induced clonic seizures. Our results showed that activation of H1 receptors by 2-(2-Pyridyl)-ethylamine exerts anticonvulsant properties while inhibition of H1 receptors by pyrilamine maleate induced proconvulsant effects. Furthermore, we showed that immepip dihydrobromide, a H3 receptor agonist, increased seizure susceptibility to PTZ whereas thioperamide, a H3 receptor antagonist increased seizure threshold. We also revealed that pretreatment with morphine potently reversed the effects of histaminergic system on seizure threshold suggesting the involvement of opioid system in alteration of seizure threshold by histaminergic drugs.

3-(1′-Cyclobutylspiro[4H-1,3-benzodioxine-2,4′-piperidine]-6-yl)-5,5-dimethyl-1,4-dihydropyridazin-6-one (CEP-32215), a new wake-promoting histamine H3 antagonist/inverse agonist

CEP-32215 is a new, potent, selective, and orally bioavailable inverse agonist of the histamine H3 receptor (H3R) with drug-like properties. High affinity in human (hH3R Ki = 2.0 ± 0.2 nM) and rat (rH3R Ki = 3.6 ± 0.7 nM) H3R radioligand binding assays was demonstrated. Potent functional antagonism (Kb = 0.3 ± 0.1 nM) and inverse agonism (EC50 = 0.6 ± 0.2 nM) were demonstrated in [35S]guanosine 5′-O-(γ-thio)-triphosphate binding assays. Oral bioavailability and dose-related exposure was consistent among rat, dog, and monkey. After oral dosing, occupancy of H3R by CEP-32215 was estimated by the inhibition of ex vivo binding in rat cortical slices (ED50 = 0.1 mg/kg p.o.). Functional antagonism in brain was demonstrated by the inhibition of R-α-methylhistamine-induced drinking in the rat dipsogenia model (ED50 = 0.92 mg/kg). CEP-32215 significantly increased wake duration in the rat EEG model at 3–30 mg/kg p.o. Increased motor activity, sleep rebound or undesirable events (such as spike wave or seizure activity) was not observed following doses up to 100 mg/kg p.o., indicating an acceptable therapeutic index. CEP-32215 may have potential utility in the treatment of a variety of sleep disorders.This article is part of the Special Issue entitled ‘Histamine Receptors’.

Pharmacological Evidence that Histamine H3 Receptors Mediate Histamine-Induced Inhibition of the Vagal Bradycardic Out-flow in Pithed Rats.

In vivo stimulation of cardiac vagal neurons induces bradycardia by acetylcholine (ACh) release. As vagal release of ACh may be modulated by autoreceptors (muscarinic M2 ) and heteroreceptors (including serotonin 5-HT1 ), this study has analysed the pharmacological profile of the receptors involved in histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats. For this purpose, 180 male Wistar rats were pithed, artificially ventilated and pre-treated (i.v.) with 1mg/kg atenolol, followed by i.v. administration of physiological saline (1ml/kg), histamine (10, 50, 100 and 200μg/kg) or the selective histamine H1 (2-pyridylethylamine), H2 (dimaprit), H3 (methimepip) and H4 (VUF 8430) receptor agonists (1, 10, 50 and 100μg/kg each). Under these conditions, electrical stimulation (3, 6 and 9Hz; 15±3V and 1ms) of the vagus nerve resulted in frequency-dependent bradycardic responses, which were (i) unchanged during the infusions of saline, 2-pyridylethylamine, dimaprit or VUF 8430; and (ii) dose-dependently inhibited by histamine or methimepip. Moreover, the inhibition of the bradycardia caused by 50μg/kg of either histamine or methimepip (which failed to inhibit the bradycardic responses to i.v. bolus injections of acetylcholine; 1-10μg/kg) was abolished by the H3 receptor antagonist JNJ10181457 (1mg/kg, i.v.). In conclusion, our results suggest that histamine-induced inhibition of the vagal bradycardic out-flow in pithed rats is mainly mediated by pre-junctional activation of histamine H3 receptors, as previously demonstrated for the vasopressor sympathetic out-flow and the vasodepressor sensory CGRPergic (calcitonin gene-related peptide) out-flow.

A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors

The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with 3H-noradrenaline and hippocampal slices with 3H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration–response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus.This article is part of the Special Issue entitled ‘Histamine Receptors’.

Impaired glutamatergic and GABAergic transmission by amitraz in primary hippocampal cells

Amitraz is a formamidine pesticide that has been reported to be a neurotoxic compound that induces convulsions among other effects. Excitatory and inhibitory neurotransmission is mediated mainly by glutamate and GABA, respectively, so their alteration could be responsible for induction of seizures. In this regard, amitraz α2 adrenergic agonist action, which has been suggested as likely responsible for this effect, could alter these neurotransmitter systems and lead to seizure induction. Moreover, other amitraz mechanisms such as histamine H1 receptor inhibition could be involved. To confirm if amitraz disrupts glutamatergic/GABAergic transmission by these mechanisms, we evaluated, in primary hippocampal neurons, the effect of amitraz (0.01μM to 100μM) with or without the α2 adrenergic antagonist idazoxan (1μM) and/or the H1 receptor agonist n-methylhistaprodifen (30μM) co-treatment on 4-aminobutyrate aminotransferase, glutamate decarboxylase 65 (GAD 65), succinate-semialdehyde dehydrogenase and glutaminase gene expression and on glutamate and GABA levels after 24h treatment. We observed that amitraz disrupts glutaminase and GAD 65 gene expression, altering glutamatergic and GABAergic transmission. These effects were mediated partially by H1 and α2 receptors suggesting that other mechanisms could be involved. These data could help explain the mechanism by which amitraz induces seizures and provide a therapeutic strategy to protect against this effect in case of poisoning.

Role of the thalamic submedius nucleus histamine H1 and H 2 and opioid receptors in modulation of formalin-induced orofacial pain in rats.

Histamine and opioid systems are involved in supraspinal modulation of pain. In this study, we investigated the effects of separate and combined microinjections of agonists and antagonists of histamine H1 and H2 and opioid receptors into the thalamic submedius (Sm) nucleus on the formalin-induced orofacial pain. Two guide cannulas were implanted into the right and left sides of the Sm in ketamine- and xylazine-anesthetized rats. Orofacial formalin pain was induced by subcutaneous injection of a diluted formalin solution (50 μl, 1.5%) into the vibrissa pad. Face rubbing durations were recorded at 3-min blocks for 45 min. Formalin produced a biphasic pain response (first phase: 0-3 min and second phase: 15-33 min). Separate and combined microinjections of histamine H1 and H2 receptor agonists, 2-pyridylethylamine (2-PEA) and dimaprit, respectively, and opioid receptor agonist, morphine, attenuated the second phase of pain. The analgesic effects induced by 2-PEA, dimaprit, and morphine were blocked by prior microinjections of fexofenadine (a histamine H1 receptor antagonist), famotidine (a histamine H2 receptor antagonist), and naloxone (an opioid receptor antagonist), respectively. Naloxone also prevented 2-PEA- and dimaprit-induced antinociception, and the analgesic effect induced by morphine was inhibited by fexofenadine and famotidine. These results showed the involvement of histamine H1 and H2 and opioid receptors in the Sm modulation of orofacial pain. Opioid receptor might be involved in analgesia induced by activation of histamine H1 and H2 receptors and vice versa.

Cardioprotective role of H3R agonist imetit on isoproterenol-induced hemodynamic changes and oxidative stress in rats

The cardioprotective role of histamine H3 receptor (H3R) agonist imetit (IMT) in isoproterenol (ISO)-induced alterations of hemodynamic and oxidative stress was investigated in Wistar rats. In this study, rats were treated with IMT (5 and 10 mg/kg, per orally [p.o.]), carvedilol (10 mg/kg, p.o.) and ISO control group (normal saline) for 7 d, with concurrent subcutaneous administration of ISO (85 mg/kg) at 24 h interval on last two consecutive days whereas control group was administered with vehicle only. ISO significantly attenuated cardiac antioxidant enzymes superoxide dismutase, catalase and increased plasma cardiac injury biomarkers creatine kinase-MB, alanine transaminase and aspartate transaminase. ISO also altered cardiac activity as evidenced by decrease in blood pressure (34.60%) and increase in heart rate (11.40%). The damage due to oxidative stress was revealed by histopathology alterations such as myocyte necrosis, myofibrillar degeneration and pyknotic nucleus. However, pre-treatment with IMT demonstrated restoration of hemodynamic alterations along with significant preservation of antioxidants and myocyte injury-specific marker enzymes. Furthermore, protective effect of IMT was reconfirmed by the histopathological salvage of myocardium. Results of the present study demonstrated the cardioprotective potential of IMT, as evidenced by favorable improvement in ISO-induced hemodynamic, plasma cardiac biomarkers and tissue antioxidant status along with maintenance of integrity of myocardium.

Involvement of histaminergic inputs in the jaw-closing reflex arc.

Histamine receptors are densely expressed in the mesencephalic trigeminal nucleus (MesV) and trigeminal motor nucleus. However, little is known about the functional roles of neuronal histamine in controlling oral-motor activity. Thus, using the whole-cell recording technique in brainstem slice preparations from Wistar rats aged between postnatal days 7 and 13, we investigated the effects of histamine on the MesV neurons innervating the masseter muscle spindles and masseter motoneurons (MMNs) that form a reflex arc for the jaw-closing reflex. Bath application of histamine (100 μM) induced membrane depolarization in both MesV neurons and MMNs in the presence of tetrodotoxin, whereas histamine decreased and increased the input resistance in MesV neurons and MMNs, respectively. The effects of histamine on MesV neurons and MMNs were mimicked by an H1 receptor agonist, 2-pyridylethylamine (100 μM). The effects of an H2 receptor agonist, dimaprit (100 μM), on MesV neurons were inconsistent, whereas MMNs were depolarized without changes in the input resistance. An H3 receptor agonist, immethridine (100 μM), also depolarized both MesV neurons and MMNs without changing the input resistance. Histamine reduced the peak amplitude of postsynaptic currents (PSCs) in MMNs evoked by stimulation of the trigeminal motor nerve (5N), which was mimicked by 2-pyridylethylamine but not by dimaprit or immethridine. Moreover, 2-pyridylethylamine increased the failure rate of PSCs evoked by minimal stimulation and the paired-pulse ratio. These results suggest that histaminergic inputs to MesV neurons through H1 receptors are involved in the suppression of the jaw-closing reflex although histamine depolarizes MesV neurons and/or MMNs.

Histamine and Histamine Receptor Involvement in Sensory‐Motor Integration of Gill Lateral Cell Cilia Activity in the Bivalve Crassostrea viginica

Gill lateral ciliated cells of Crassostrea virginica are innervated by serotonin and dopamine nerves. Motor aspects have been well studied, but the sensory side hasn't. Histamine (HIS) a neurotransmitter in a variety of invertebrates rarely has been reported in bivalves. We quantified HIS in C. virginica and found gill lateral cell cilia beating changed in response to mantle sensory inputs including HIS. The mechanism involves mantle rim sensory tentacles and visceral ganglia. HIS does not alter beating when applied to gill. We hypothesize HIS receptors are present in mantle and can be confirmed by Western Blot (WB). For WB, mantle body and rim lysates were prepared in NP-40 detergent buffer containing protease inhibitor followed by centrifuging to obtain supernatant with solubilized mantle body and rim membrane proteins. H2 receptor immunoreactivity was revealed by 1̊ antibody followed by HRP-conjugated 2̊ antibody. Mantle body and rim H2 receptor protein was resolved by colormetric development using CN/DAB substrate kit. We also did a dose response of HIS H1, H2 and H3 receptor agonists and antagonist at the mantle rim and observed cilia beating in gill. WB showed a 70 kD band corresponding to HIS H2 receptors in mantle body and rim, and H2 agonists and antagonists had the strongest effects on cilia beating. The study shows mantle body and rim have HIS H2 receptors and demonstrates a physiological role of HIS in sensory-motor integration of gill lateral cell cilia activity.

Lipoxin A4 Inhibits Histamine‐stimulated Increase in [Ca2+] and Mucin Secretion in Cultured Rat and Human Goblet Cells

In allergic conjunctivitis histamine levels are elevated and goblet cell mucin secretion stimulated. The purpose of this study was to determine if the effects of histamine can be blocked by the pro‐resolution compound lipoxin A4 (LXA4) in cultured conjunctival goblet cells (GCs), similar to pro‐resolution effects of resolvin D1 (RvD1). First passage GCs from rat and human were used. Intracellular [Ca2+] ([Ca2+]i) was measured using fura2. LXA4 (10‐11‐10‐8M) was added alone or 0.5h prior to histamine (10‐5M). In rat GCs, LXA4 alone increased [Ca2+]i a maximum of 116.4±21.5 nM above basal which was significantly inhibited by the ALX receptor inhibitor BOC‐2. In human GCs, LXA4 increased [Ca2+]i a maximum of 762.0±259.4nM above basal which was inhibited by BOC‐2. LXA4 inhibited histamine‐stimulated increase in [Ca2+]i by 63.7±10.2% and 71.0±7.7% in rat and human CGs, respectively. In rat GCs, stimulation with the specific H1 receptor agonist histamine dimaleate stimulated [Ca2+]i by 751.7±216.1 nM. This was inhibited by LXA4 by 70.5±8.9%. Preincubation with an inhibitor to b‐adrenergic receptor kinase 1 (βARK1), but not inhibition of protein kinase C by Ro31754, reversed LAX4 inhibition of histamine dimaleate response. We conclude that similarly to RvD1, LXA4 functions as a pro‐resolution mediator as it inhibits histamine‐stimulated responses by counter‐regulation of the H1 histamine receptor through βARK1. LXA4 could play a role in the return of GCs to homeostasis in allergic conjunctivitis.

Activation of histamine H3 receptor decreased cytoplasmic Ca2+ imaging during electrical stimulation in the skeletal myotubes

Histamine is a neurotransmitter and chemical mediator in multiple physiological processes. Histamine H3 receptor is expressed in the nervous system, heart, and gastrointestinal tract; however, little is known about H3 receptor in skeletal muscle. The aim of this study was to investigate the role of H3 receptor in skeletal myotubes. The expression of H3 receptor and myosin heavy chain (MHC), a late myogenesis marker, was assessed by real-time PCR and immunostaining in C2C12 skeletal myogenesis and adult mid-urethral skeletal muscle tissues. H3 receptor mRNA showed a significant increase upon differentiation of C2C12 into myotubes: 1-, 26-, 91-, and 182-fold at days 0, 2, 4, and 6, respectively. H3 receptor immunostaining in differentiated C2C12 cells and adult skeletal muscles was positive and correlated with that of MHC. The functional role of H3receptor in differentiated myotubes was assessed using an H3 receptor agonist, (R)-a-methylhistamine ((R)-α-MeHA). Ca2+ imaging, stimulated by electric pacing, was decreased by 55% after the treatment of mature C2C12 myotubes with 1μM (R)-α-MeHA for 10min and 20min, while treatment with 100nm (R)-α-MeHA for 5min caused 45% inhibition. These results suggested that H3 receptor may participate in the maintenance of the relaxed state and prevention of over-contraction in mature differentiated myotubes. The elucidation of the role of H3R in skeletal myogenesis and adult skeletal muscle may open a new direction in the treatment of skeletal muscle disorders, such as muscle weakness, atrophy, and myotonia in motion systems or peri-urethral skeletal muscle tissues.

Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists

The bioisosteric replacement of the acylguanidine moieties in dimeric histamine H2 receptor (H2R) agonists by carbamoylguanidine groups resulted in compounds with retained potencies and intrinsic activities, but considerably improved stability against hydrolytic cleavage. These compounds achieved up to 2500 times the potency of histamine when studied in [35S]GTPγS assays on recombinant human and guinea pig H2R. Unlike 3-(imidazol-4-yl)propyl substituted carbamoylguanidines, the corresponding 2-amino-4-methylthiazoles revealed selectivity over histamine receptor subtypes H1R, H3R and H4R in radioligand competition binding studies. H2R binding studies with three fluorescent compounds and one tritium-labeled ligand, synthesized from a chain-branched precursor, failed due to pronounced cellular accumulation and high non-specific binding. However, the dimeric H2R agonists proved to be useful pharmacological tools for functional studies on native cells, as demonstrated for selected compounds by cAMP accumulation and inhibition of fMLP-stimulated generation of reactive oxygen species in human monocytes.

The Effect of Subchronic Dosing of Ciproxifan and Clobenpropit on Dopamine and Histamine Levels in Rats.

The present study was designed to investigate the effect of once daily for 7-day (subchronic treatment) dosing of histamine H3 receptor antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p), including clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively, on MK-801(0.2 mg/kg, i.p.)-induced locomotor activity, and dopamine and histamine levels in rats. Dopamine and histamine levels were measured in striatum and hypothalamus, respectively, of rat brain. Atypical and typical antipsychotics were used to serve as clinically relevant reference agents to compare the effects of the H3 receptor antagonists. MK-801-induced increase of horizontal activity was reduced with CPX and CBP. The attenuation of MK-801-induced locomotor hyperactivity produced by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised dopamine levels in the striatum, which was reduced in rats pretreated with CPX and CBP. CPZ also lowered striatal dopamine levels, though the decrease was less robust compared to CLZ, CPX and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increase in histamine levels in the hypothalamus compared to the MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.) counteracted the effects of CPX and CBP. In conclusion, the subchronic dosing of CPX/CBP suggests some antipsychotic-like activities as CPX/CBP counteracts the modulatory effects of MK-801 on dopamine and histamine levels and prevents MK-801-induced hyperlocomotor behaviors.

Cerebellar vermis H2 receptors mediate fear memory consolidation in mice

Histaminergic fibers are present in the molecular and granular layers of the cerebellum and have a high density in the vermis and flocullus. Evidence supports that the cerebellar histaminergic system is involved in memory consolidation. Our recent study showed that histamine injections facilitate the retention of an inhibitory avoidance task, which was abolished by pretreatment with an H2 receptor antagonist. In the present study, we investigated the effects of intracerebellar post training injections of H1 and H2 receptor antagonists as well as the selective H2 receptor agonist on fear memory consolidation. The cerebellar vermi of male mice were implanted with guide cannulae, and after three days of recovery, the inhibitory avoidance test was performed. Immediately after a training session, animals received a microinjection of the following histaminergic drugs: experiment 1, saline or chlorpheniramine (0.016, 0.052 or 0.16nmol); experiment 2, saline or ranitidine (0.57, 2.85 or 5.07nmol); and experiment 3, saline or dimaprit (1, 2 or 4nmol).Twenty-four hours later, a retention test was performed. The data were analyzed using one-way analysis of variance (ANOVA) and Duncan’s tests. Animals microinjected with chlorpheniramine did not show any behavioral effects at the doses that we used. Intra-cerebellar injection of the H2 receptor antagonist ranitidine inhibited, while the selective H2 receptor agonist dimaprit facilitated, memory consolidation, suggesting that H2 receptors mediate memory consolidation in the inhibitory avoidance task in mice.

Olanzapine-activated AMPK signaling in the dorsal vagal complex is attenuated by histamine H1 receptor agonist in female rats.

Weight gain and its related metabolic disorders are major side effects associated with second generation antipsychotic drug treatment. The dorsal vagal complex (DVC) and AMP-activated protein kinase (AMPK) are implicated in the regulation of food intake and body weight. Blocking the histamine H1 receptor contributes to antipsychotic-induced weight gain. The present study investigated the time-dependent effect of olanzapine treatment (8, 16, and 36 d) on DVC AMPK signaling in olanzapine-induced weight gain and whether these changes are associated with olanzapine-induced H1 receptor antagonism. During the 8-day olanzapine treatment, the rats were hyperphagic and rapidly gained weight. The phosphorylation of AMPK (pAMPK) (activated AMPK) as well as its directly downstream phospho-acetyl-coenzyme A carboxylase was significantly increased. The pAMPK/AMPK ratio, an indicator of AMPK activity, was significantly positively correlated with feeding efficiency and weight gain. As treatment was prolonged (16 and 36 d of olanzapine treatment), the rats were no longer hyperphagic, and there were no longer any changes in DVC AMPK signaling. Although the DVC H1 receptor protein expression was not significantly altered by olanzapine, the pAMPK expression was significantly positively correlated with the H1 receptor level after the 8-, 16-, and 36-day olanzapine treatments. Moreover, we showed that an H1 receptor agonist, 2-(3-trifluoromethylphenyl) histamine, significantly inhibited the olanzapine-induced hyperphagia and DVC AMPK activation in a dose-dependent manner. These results suggest a time-dependent role of DVC AMPK in olanzapine-induced obesity. Thus, olanzapine-induced DVC AMPK activation may be at least partially related to olanzapine's antagonistic effect on the H1 receptor.

The H3 receptor agonist immepip does not affect l-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats

The treatment of dyskinesia in Parkinson׳s disease remains poor but H3 receptor agonists have been suggested as a novel pharmacological approach. We examined the effects of the H3 agonist, immepip, in 6-OHDA-lesioned rats exhibiting AIMs (abnormal involuntary movements), a rat analogue of dyskinesia, in response to l-dopa compared to the known anti-dyskinetic agents amantadine, MK-801 and 8-OHDPAT. We then attempted to extend these studies in to dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated common marmosets.Amantadine, MK-801 and 8-OHDPAT all dose-dependently reduced l-dopa-induced axial, lingual and oral (ALO) AIMs in 6-OHDA-lesioned animals accompanied by a reduction in contralateral rotation with higher doses of amantadine and MK-801. By contrast, immepip had no effect on AIMs expression or contralateral rotation. In the MPTP-treated common marmoset exhibiting dyskinesia to l-dopa, immepip alone induced retching and in combination with l-dopa administered subcutaneously or orally induced the rapid onset of retching and vomiting which was not controlled by pretreatment with domperidone. Administration of the unrelated H3 agonist, imetit had the same effect. Despite causing negative side-effects, it appears that both agonists reduced the antiparkinsonian response to l-dopa resulting in reduced dyskinesia.H3 agonists appear unlikely candidates for the treatment of dyskinesia in PD based on lack of evidence of efficacy and potential adverse effects.

(R)‐alpha‐methylhistamine Suppresses Inhibitory Neurotransmission in Hippocampal CA1 Pyramidal Neurons Counteracting Propofol‐Induced Amnesia in Rats

Propofol is a short-acting, intravenous general anesthetic that is widely used in clinical practice for short procedures; however, it causes depressed cognitive function for several hours thereafter. (R)-alpha-methylhistamine (RAMH), a selective histamine H3 receptor agonist, can enhance memory retention and attenuates memory impairment in rats. In this study, we investigated whether RAMH could rescue propofol-induced memory deficits and the underlying mechanisms partaking in this process. In the modified Morris water maze (MWM) test, rats were randomized into the following groups: control, propofol (25mg/kg, i.p., 30min before training), RAMH (10mg/kg, i.p., 60min before training), and propofol plus RAMH. All randomized rats were subjected to 2days of training, and a probe test was conducted on day 3. Field excitatory postsynaptic potentials were recorded from CA1 neurons in rat hippocampal slices, and long-term potentiation (LTP) was induced by either theta-burst stimulation (TBS) or high-frequency tetanic stimulation (HFS). Spontaneous and miniature inhibitory (sIPSCs, mIPSCs) or excitatory (sEPSCs, mEPSCs) postsynaptic currents were recorded from CA1 pyramidal neurons by whole-cell patch clamp. In the MWM task, propofol injection significantly impaired spatial memory retention. Pretreatment with RAMH reversed propofol-induced memory retention. In hippocampal CA1 slices, propofol perfusion markedly inhibited TBS- but not HFS-induced LTP. Co-perfusion of RAMH reversed the inhibitory effect of propofol on TBS-induced LTP reduction. Furthermore, in hippocampal CA1 pyramidal neurons, RAMH significantly suppressed the frequency but not the amplitude of sIPSCs and mIPSCs and had little effects on both the frequency and amplitude of sEPSCs and mEPSCs. Our results suggest that RAMH, by inhibiting presynaptic GABAergic neurotransmission, suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons, which in turn reverses inhibition of CA1 LTP and the spatial memory deficits induced by propofol in rats.

Betahistine ameliorates olanzapine-induced weight gain through modulation of histaminergic, NPY and AMPK pathways.

Olanzapine is widely used to treat schizophrenia and other disorders, but causes adverse obesity and other metabolic side-effects. Both animal and clinical studies have shown that co-treatment with betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for ameliorating olanzapine-induced weight gain/obesity. To reveal the mechanisms underlying these effects, this study investigated the effects of co-treatment of olanzapine and betahistine (O+B) on expressions of histaminergic H1 receptor (H1R), AMP-activated protein kinase (AMPK), neuropeptide Y (NPY), and proopiomelanocortin (POMC) in the hypothalamus associated with reducing olanzapine-induced weight gain. Olanzapine significantly upregulated the mRNA and protein expressions of H1R, while O+B co-treatment significantly downregulated the H1R levels, compared to the olanzapine-only treatment group. The NPY mRNA expression was significantly enhanced by olanzapine, but it was significantly reversed by O+B co-treatment. The hypothalamic H1R expression was positively correlated with total food intake, and NPY expression. Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation (pAMPKα)/AMPKα ratio compared with controls, whereas O+B co-treatment decreased the pAMPKα/AMPKα ratio, compared with olanzapine only treatment. The pAMPKα/AMPKα ratio was positively correlated with total food intake and H1R expression. Although olanzapine administration decreased the POMC mRNA level, this level was not affected by O+B co-treatment. Therefore, these results suggested that co-treatment with betahistine may reverse olanzapine-induced body weight gain via the H1R-NPY and H1R-pAMPKα pathways.