Bath Application Of Histamine Research Articles

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.

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

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

Histamine excites rat lateral vestibular nuclear neurons through activation of post-synaptic H2 receptors

Through whole-cell patch recordings in brainstem slices, the effects of histamine on neuronal activity of the lateral vestibular nucleus (LVN) were investigated. Bath application of histamine elicited a concentration-dependent excitation of both spontaneous firing (n=19) and silent (n=7) LVN neurons. Moreover, histamine induced a stable inward current in the LVN neurons (n=5) and the histamine-induced depolarization of membrane potential persisted in the presence of tetrodotoxin (n=4), indicating a direct post-synaptic effect of the histamine on the LVN neurons. Selective histamine H2 receptor antagonist ranitidine effectively blocked the histamine-evoked excitatory responses on the LVN neurons (n=4), but selective histamine H1 receptor antagonist triprolidine did not (n=4). In addition, selective histamine H2 receptor agonist dimaprit (n=3) rather than 2-pyridylethylamine (n=4), a selective histamine H1 receptor agonist, mimicked the excitatory action of histamine on LVN neurons. The results demonstrate that histamine excites the LVN neurons via post-synaptic histamine H2 receptors and suggest that the central histaminergic projection arising from the hypothalamus may modulate LVN neurons activity and actively influence the vestibular reflexes and functions.

Histamine-Induced Excitatory Responses in Mouse Ventromedial Hypothalamic Neurons: Ionic Mechanisms and Estrogenic Regulation

Histamine is capable of modulating CNS arousal states by regulating neuronal excitability. In the current study, histamine action in the ventromedial hypothalamus (VMH), its related ionic mechanisms, and its possible facilitation by estrogen were investigated using whole cell patch-clamp recording in brain slices from ovariectomized female mice. Under current clamp, a bath application of histamine (20 microM) caused membrane depolarization, associated with an increased membrane resistance. In some cells, the depolarization was accompanied by action potentials. Histamine application also significantly reduced the latency of action potential evoked by current steps. Histamine-induced depolarization was not affected by either tetrodotoxin or Cd(2+). However, after blocking K(+) channels with tetraethylammonium, 4-aminopyridine, and Cs(+), depolarization was significantly decreased. Under voltage clamp, histamine-induced depolarization was associated with an inward current. The current-voltage relationship revealed that this inward current reversed near E(K). The histamine effect was mimicked by a histamine receptor 1 (H(1)) agonist, but not a histamine receptor 2 (H(2)) agonist. An H(1) antagonist, but not H(2) antagonist, abolished histamine responses. When ovariectomized mice were treated with estradiol benzoate (E2), histamine-induced depolarization was significantly enhanced with an increased percentage of cells showing action potential firing. These results suggest that histamine depolarized VMH neurons by attenuating a K(+) leakage current and this effect was mediated by H(1) receptor. E2 facilitated histamine-induced excitation of VMH neurons. This histamine effect may present a potential mechanism by which estrogens modulate the impact of generalized CNS arousal on a sexual arousal-related neuronal group.

P.1.c.005 Polymorphism of the serotonin transporter promoter may predict the response to selective serotonin reuptake inhibitors in bulimia nervosa

Conventional intracellular microelectrodes and marker injection techniques were used to study the actions of histamine on inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine. Bath application of histamine (1–300 μM) reversibly suppressed both noradrenergic and non-adrenergic slow inhibitory postsynaptic potentials in a concentration-dependent manner. These effects of histamine were mimicked by the selective histamine H3 receptor agonist R(−)-α-methylhistamine but not the selective histamine H1 receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT dimaleate), or the selective histamine H2 receptor agonist, dimaprit. The histamine H3 receptor antagonist, thioperamide, blocked the effects of histamine. Histamine H1 and H2 receptor antagonists did not change the action of histamine. Hyperpolarizing responses to focal application of norepinephrine or somatostatin by pressure ejection from micropipettes were unaffected by histamine and R(−)-α-methylhistamine. The results suggest that histamine acts at presynaptic histamine H3 receptors on the terminals of sympathetic postganglionic fibers and intrinsic somatostatinergic nerves in the small intestine to suppress the release of the inhibitory neurotransmitters, norepinephrine and somatostatin.

Histamine Excites Neonatal Rat Sympathetic Preganglionic Neurons In Vitro Via Activation of H1 Receptors

The role of histamine in regulating excitability of sympathetic preganglionic neurons (SPNs) and the expression of histamine receptor mRNA in SPNs was investigated using whole-cell patch-clamp electrophysiological recording techniques combined with single-cell reverse transcriptase polymerase chain reaction (RT-PCR) in transverse neonatal rat spinal cord slices. Bath application of histamine (100 microM) or the H1 receptor agonist histamine trifluoromethyl toluidide dimaleate (HTMT; 10 microM) induced membrane depolarization associated with a decrease in membrane conductance in the majority (70%) of SPNs tested, via activation of postsynaptic H1 receptors negatively coupled to one or more unidentified K+ conductances. Histamine and HTMT application also induced or increased the amplitude and/or frequency of membrane potential oscillations in electrotonically coupled SPNs. The H2 receptor agonist dimaprit (10 microM) or the H3 receptor agonist imetit (100 nM) were without significant effect on the membrane properties of SPNs. Histamine responses were sensitive to the H1 receptor antagonist triprolidine (10 microM) and the nonselective potassium channel blocker barium (1 mM) but were unaffected by the H2 receptor antagonist tiotidine (10 microM) and the H3 receptor antagonist, clobenpropit (5 microM). Single cell RT-PCR revealed mRNA expression for H1 receptors in 75% of SPNs tested, with no expression of mRNA for H2, H3, or H4 receptors. These data represent the first demonstration of H1 receptor expression in SPNs and suggest that histamine acts to regulate excitability of these neurons via a direct postsynaptic effect on H1 receptors.

Histaminergic modulation of excitatory synaptic transmission in the rat basolateral amygdala

The effects of histamine on excitatory synaptic transmission between the external capsule and basolateral amygdala (BLA) were examined using intracellular and field potential recordings in rat amygdala slices. Bath application of histamine (20 μM) suppressed intracellular excitatory postsynaptic potentials (EPSPs; 70.3±5.1% of control amplitude) in 43 of 64 BLA neurons, and potentiated EPSPs (341±81% of control amplitude) in 21 neurons, without changing resting membrane potential or input resistance. The histamine-induced suppression of EPSPs was accompanied by an increase in paired-pulse facilitation of the slopes of EPSPs, suggesting a presynaptic locus of the action. The suppressive effect could be blocked by the selective H 3 antagonist thioperamide, and mimicked by the selective H 3 agonist R-α-methylhistamine, indicating that the suppressive effect is mediated by the presynaptic H 3 receptor. The potentiating effect of histamine on EPSPs was not accompanied by the change of paired-pulse facilitation and was not affected by the presence of H 1, H 2 or H 3 receptor antagonists. In addition, the effective concentration of agonist to produce 50% of maximal response (EC 50) of the potentiating action of histamine is 49 nM, much lower than the EC 50 (470 nM) of the H 3 receptor-mediated suppressive effect characterized here. These observations suggest a novel, high affinity and postsynaptically mediated effect of histamine. In extracellular recordings, histamine, at low concentration (200 nM), consistently potentiated field potentials. At high concentration (20 μM), histamine suppressed field potentials, but potentiated field potentials when H 3 receptors were blocked. Taken together, these results revealed that histamine, via the presynaptic H 3 receptor and a currently unknown mechanism, decreases or increases excitatory synaptic transmission in the BLA respectively. This specific histaminergic modulation of neuronal activity in the amygdala may play an important role in amygdala-mediated physiological and pathophysiological processes, such as fear, emotional learning and memory, temporal lobe epilepsy, and affective disorders.

Histamine H 3 receptors depress synaptic transmission in the corticostriatal pathway

The effect of histamine on the main input to the striatum — the corticostriatal pathway — was studied using electrophysiological techniques in brain slices from rats and mice. Field potentials (FPs) were recorded in the striatum following stimulation at the border of the striatum and the cortex. Bath application of histamine caused a pronounced and long-lasting depression of FPs in rat slices with an IC 50 of 1.6 μM and a maximal depression of around 40%. In mouse slices histamine also depressed FPs, but to a lesser extent and more transiently. Further experiments in rat slices showed that histamine H 3 receptors were responsible for this depression since the selective H 3 receptor agonist R-α-methylhistamine (1 μM) mimicked the action of histamine whilst the selective H 3 receptor antagonist, thioperamide (10 μM) blocked the depression caused by histamine application. The histaminergic depression was probably not mediated indirectly through interneurons since blockade of GABA A, GABA B, nicotinic and muscarinic receptors or nitric oxide synthase did not prevent the histamine effect. Intracellular recordings from medium spiny neurons in the striatum revealed that histamine did not affect postsynaptic membrane properties but increased paired-pulse facilitation of excitatory synaptic responses indicating a presynaptic locus of action.

Histamine depolarizes cholinergic interneurones in the rat striatum via a H(1)-receptor mediated action.

1. Whole-cell patch clamp recordings were made from rat striatal cholinergic interneurones in slices of brain tissue in vitro. Bath application of histamine (EC(50) 6.3 microM) was found to rapidly and reversibly depolarize these neurones through the induction of an inward current at -60 mV. 2. The effects of histamine were mimicked by the H(1) receptor agonist 2-thiazolylethylamine (50 microM) and selectively inhibited by pre-incubation with the H(1) receptor antagonist triprolidine (1 microM). 3. Ion substitution experiments under voltage clamp conditions revealed that the histamine activated current was comprised of two components. One component was sensitive to the concentration of extracellular Na(+), whilst the other component was inhibited by intracellular Cs(+) or extracellular Ba(2+). 4. In situ hybridization experiments revealed that the majority of cholinergic interneurones in the rat striatum express the histamine H(1) receptor but few neurones express H(2) receptors. These findings were confirmed using single cell RT - PCR. 5. It is concluded that histamine depolarizes cholinergic interneurones in the rat striatum via a H(1)-receptor mediated mechanism.

Histamine H 3 receptor-mediated suppression of inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine

Conventional intracellular microelectrodes and marker injection techniques were used to study the actions of histamine on inhibitory synaptic transmission in the submucous plexus of guinea-pig small intestine. Bath application of histamine (1–300 μM) reversibly suppressed both noradrenergic and non-adrenergic slow inhibitory postsynaptic potentials in a concentration-dependent manner. These effects of histamine were mimicked by the selective histamine H 3 receptor agonist R(−)-α-methylhistamine but not the selective histamine H 1 receptor agonist, 6-[2-(4-imidazolyl)ethylamino]- N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT dimaleate), or the selective histamine H 2 receptor agonist, dimaprit. The histamine H 3 receptor antagonist, thioperamide, blocked the effects of histamine. Histamine H 1 and H 2 receptor antagonists did not change the action of histamine. Hyperpolarizing responses to focal application of norepinephrine or somatostatin by pressure ejection from micropipettes were unaffected by histamine and R(−)-α-methylhistamine. The results suggest that histamine acts at presynaptic histamine H 3 receptors on the terminals of sympathetic postganglionic fibers and intrinsic somatostatinergic nerves in the small intestine to suppress the release of the inhibitory neurotransmitters, norepinephrine and somatostatin.

Inositol 1,4,5-trisphosphate-sensitive Ca 2+ stores in rat supraoptic neurons: involvement in histamine-induced enhancement of depolarizing afterpotentials

Histamine, a putative neuromodulator and neurotransmitter, can depolarize supraoptic neurons and enhance depolarizing afterpotentials that play a key role in determining the excitability of these neurons. This study investigated intracellular signal transduction involved in histamine-induced enhancement of depolarizing afterpotentials utilizing immunohistochemical and electrophysiological methods. Abundant inositol 1,4,5-trisphosphate receptor-related immunostaining was seen in all parts of the supraoptic nucleus, mainly within somata and proximal processes of the magnocellular neurons, but also in astrocytes of the ventral glial lamina. In supraoptic neurons displaying depolarizing afterpotentials, three brief depolarizations evoked a slow inward current. Bath application of histamine (1–2.5 μM) reversibly enhanced this slow inward current in almost all supraoptic neurons tested. Amplitudes and durations of the slow inward current were increased by 68.1% and 22.8%, respectively. Pretreatment of cells with a histamine receptor (subtype 1) antagonist (pyrilamine) or inhibitors of phospholipase C activation (neomycin or U73122) prevented histamine-induced enhancement of the slow inward current. When electrodes containing heparin, an inositol 1,4,5-trisphosphate receptor blocker, were used for recording, histamine had no effect on the slow inward current. Heparin, however, failed to abolish norepinephrine-induced enhancement of the slow inward current. After H 7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine], an inhibitor of protein kinase C, was infused into supraoptic neurons via the electrodes, histamine-induced enhancement of the slow inward current was also blocked. These results indicate the presence of, and functional roles for, inositol 1,4,5-trisphosphate receptor-sensitive Ca 2+ stores in supraoptic neurons. Following activation of histamine receptors (subtype 1) and phospholipase C, Ca 2+ mobilization from internal stores participates in mediating histamine-induced enhancement of depolarizing afterpotentials.

Histamine increases the bursting activity of pyramidal cells in the CA3 region of mouse hippocampus

An excitatory action of histamine was investigated by intracellular recording in the CA3 region of hippocampal slices. Bath application of histamine or impromidine, a H2 receptor agonist, had the following effects: (1) a depolarisation in 60% and no changes in membrane potential in 40% of the CA3 pyramids; (2) single cell firing and burst activity were evoked or more than doubled when spontaneously present; (3) the bursts were prolonged and often followed by afterdischarges instead of the normal afterhyperpolarisations (AHPs); (4) synaptic stimulation evoked large bursts instead of excitatory synaptic potentials (EPSPs) and primary burst responses became prolonged. CA3 bursts may play a decisive role in memory trace formation, their facilitation and potentiation is in keeping with a positive role of the histaminergic system in attention and learning.

Histamine-induced prolonged depolarization in rat supraoptic neurons: G-protein-mediated, Ca(2+)-independent suppression of K+ leakage conductance.

Ionic mechanisms responsible for histamine-induced prolonged depolarization in supraoptic nucleus neurons were investigated using whole-cell patch recordings in horizontally prepared brain slices from adult male rats. Bath application of histamine (1-10 microM) in control medium induced membrane depolarization in nine of 12 phasically firing, putative vasopressin cells, but not in continuous firing, putative oxytocin cells (none of five cells). Depolarization, usually accompanied by increased firing rate, started within 20 s after histamine reached the slices, lasting for 3-13 min, after which they repolarized, and this was repeatable upon washout. Chelation of intracellular Ca2+ with 11 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetra-acetate and perfusion of slices with Ca(2+)-free medium blocked neither histamine-induced membrane depolarizations nor increased firing rates in 24 of 30 cells recorded. Depolarizations were always associated with decreases in membrane conductance. Following treatment with promethazine (H1 receptor antagonist) in six cells excited previously by histamine, subsequent application induced neither membrane depolarization nor increased firing. H1 receptor agonists mimicked histamine-induced depolarization (four of six cells) but the H2 receptor agonist, dimaprit (10 microM), had no effect (all of nine cells). In medium containing 0 mM Ca2+, 2 mM Co2+ and 1-2 microM tetrodotoxin, with internal Ca2+ chelation, bath application of histamine induced an apparent inward current in 15 of 20 supraoptic neurons tested. The peak of inward current evoked by 1-10 microM histamine at holding potentials around -50 mV varied from 10 to 50 pA (27.3 +/- 0.3 pA, mean +/- S.E.M.). Ramp voltage tests revealed that this inward current decreased as membrane potential was hyperpolarized and had a reversal potential of -90.1 +/- 3.8 mV (n = 10). Subtraction of current obtained before from that during histamine application revealed a current that was linear against membrane potential. Increasing external K+ concentration or introduction of K+ channel blockers in the medium attenuated or abolished histamine-induced inward current at membrane potentials close to -50 mV. When external Cl- concentration was reduced, histamine-induced inward current was still seen in five of seven supraoptic cells tested. Neither inward current nor change in conductance was observed following bath application of histamine in 11 of 12 neurons recorded using patch pipettes containing guanosine 5'-O-(2-thiodiphosphate), and in seven of eight neurons using pipettes containing guanosine 5'-O-(3-thiotriphosphate). These results suggest that histamine depolarizes supraoptic neurons, at least in part, by inhibiting a K+ leakage current mediated by H1 receptors linked to GTP-binding proteins and Ca(2+)-independent pathways. This study provides initial evidence for the second messengers regulating K+ leakage current.

Effects of histamine and betahistine on rat medial vestibular nucleus neurones: possible mechanism of action of anti-histaminergic drugs in vertigo and motion sickness.

The tonic discharge of 71 medial vestibular nucleus (MVN) neurones was recorded in slices of the dorsal brainstem of young adult rats. Bath application of histamine caused a dose-related excitation in 59 of the 71 cells (83%), the remaining 12 (17%) being unresponsive. Dimaprit, a selective H2 agonist, also caused excitation in all 20 cells tested. The histamine-induced excitation and the response to dimaprit were antagonised by the selective H2 antagonist ranitidine, confirming that the H2 subtype of histamine receptor is involved in mediating the effects of histamine on these cells. Triprolidine, a selective H1 antagonist, also antagonised the excitation caused by histamine, at a concentration (0.3 microM) which left the H2 receptor-mediated response to dimaprit unchanged. Thus the excitatory effects of histamine on MVN cells in the rat involve two components mediated through H1 and H2 receptor-linked mechanisms, respectively. Betahistine, a weak H1 agonist and H3 antagonist, had little excitatory action when applied on its own, but significantly reduced the excitation caused by histamine when the two drugs were applied together. The effects of betahistine were consistent with a partial-agonist action at H1 receptors on MVN cells, reducing the excitatory responses to histamine presumably by occupying these receptor sites in competition with the exogenously applied neurotransmitter. This partial-agonist action of betahistine may be an important part of its mechanism of action in the symptomatic treatment of vertigo and motion sickness, since it is likely to occur not only in the MVN but also in many brain regions, including the thalamus and cortex, which express H1 receptors and which are innervated by the hypothalamic histaminergic system. Thus the effectiveness of betahistine and other anti-H1 drugs against motion sickness may be explained by their action in reducing the effects of the excess histamine release induced in such conditions in various brain areas, including the MVN.

Medial vestibular nucleus in the guinea-pig: histaminergic receptors. I. An in vitro study.

Antihistaminergic drugs are currently used for the symptomatic treatment of vestibular-related syndromes such as vertigo and motion sickness. We therefore investigated whether histamine could modulate the firing of medial vestibular nuclei neurons (MVNn). Recently, we have demonstrated that different cell types are present among MVNn in guinea-pig brainstem slices. Bath-application of histamine at 10(-4) or 10(-5) M induced a small membrane depolarization accompanied by a slight decrease in membrane resistance and a reversible increase in spontaneous firing in all MVN cell types. These effects were presumably postsynaptic as they persisted in a low-calcium/high-magnesium solution. Using a variety of agonists and antagonists of histamine receptors (H1, H2 and H3), we conclude that these effects are mediated by H2 receptors. The companion paper is concerned with an in vivo study of the histaminergic modulation of the vestibular function (Yabe et al., in press).

Histamine excites pedunculopontine neurones in guinea pig brainstem slices

Intracellular recordings were obtained from pedunculopontine tegmental nuclei neurones in guinea pig brainstem slices. These neurones were characterized by the presence of a slow regular firing (around 3 spikes/s), a broad action potential (more than 1 ms) and a transient rectification indicating the presence of an A current. Bath-application of histamine at 10 −4 or 10 −5 M induced a reversible increase in spontaneous firing. In presence of tetrodotoxine (1 μM), the effect of histamine was a reversible membrane depolarization. It was a direct effect as it persisted in presence of a low calcium/high magnesium solution. This excitatory action was presumably mediated by histamine H 1 receptors as it could be blocked by the H 1 receptor antagonist mepyramine but not by the H 2 receptor antagonist cimetidine. A role in arousal is discussed.