Histamine: action on supraoptic and other hypothalamic neurones of the cat

Histamine-releasing neurons are located exclusively in the TM of the hypothalamus, from where they project to practically all brain regions, with ventral areas (hypothalamus, basal forebrain, amygdala) receiving a particularly strong innervation. The intrinsic electrophysiological properties of TM neurons (slow spontaneous firing, broad action potentials, deep afterhyperpolarisations, etc.) are extremely similar to other aminergic neurons. Their firing rate varies across the sleep-wake cycle, being highest during waking and lowest during rapid-eye movement sleep. In contrast to other aminergic neurons somatodendritic autoreceptors (H₃) do not activate an inwardly rectifying potassium channel but instead control firing by inhibiting voltage-dependent calcium channels. Histamine release is enhanced under extreme conditions such as dehydration or hypoglycemia or by a variety of stressors. Histamine activates four types of receptors. H₁ receptors are mainly postsynaptically located and are coupled positively to phospholipase C. High densities are found especially in the hypothalamus and other limbic regions. Activation of these receptors causes large depolarisations via blockade of a leak potassium conductance, activation of a non-specific cation channel or activation of a sodium–calcium exchanger. H₂ receptors are also mainly postsynaptically located and are coupled positively to adenylyl cyclase. High densities are found in hippocampus, amygdala and basal ganglia. Activation of these receptors also leads to mainly excitatory effects through blockade of calcium-dependent potassium channels and modulation of the hyperpolarisation-activated cation channel. H₃ receptors are exclusively presynaptically located and are negatively coupled to adenylyl cyclase. High densities are found in the basal ganglia. These receptors mediated presynaptic inhibition of histamine release and the release of other neurotransmitters, most likely via inhibition of presynaptic calcium channels. Finally, histamine modulates the glutamate NMDA receptor via an action at the polyamine binding site. The central histamine system is involved in many central nervous system functions: arousal; anxiety; activation of the sympathetic nervous system; the stress-related release of hormones from the pituitary and of central aminergic neurotransmitters; antinociception; water retention and suppression of eating. A role for the neuronal histamine system as a danger response system is proposed.

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 H₇ [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 Ca²⁺ stores in supraoptic neurons. Following activation of histamine receptors (subtype 1) and phospholipase C, Ca²⁺ mobilization from internal stores participates in mediating histamine-induced enhancement of depolarizing afterpotentials.

Concentrations of norepinephrine and metabolites of biogenic amines were measured in lumbar cerebrospinal fluid of 30 patients with chronic schizophrenia, nine of whom were polyuric. The mean level of norepinephrine was two-fold higher (p≤0.025) in polyuric patients than in patients whose excretion of urine was within the normal range. CSF levels of histamine's primary metabolite, tele-methylhistamine, an index of brain histaminergic activity, were positively correlated (p<0.005) with daily urine volume. These results are consistent with the known influence of norepinephrine and histamine on fluid regulation and suggest that norepinephrine and histamine may be involved in psychogenic polydipsia-polyuria in schizophrenic patients.

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 μM) 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 Ca²⁺-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 μM), had no effect (all of nine cells). In medium containing 0 mM Ca²⁺, 2 mM Co²⁺ and 1–2 μM 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 μM 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 Ca²⁺-independent pathways. This study provides initial evidence for the second messengers regulating K⁺ leakage current.

Axons from the histaminergic neurons of the tuberomammillary nucleus project to both the anterior and tuberal portions of the supraoptic nucleus. Histamine is known to activate vasopressin neurons via a histamine receptor subtype 1 and to increase release of vasopressin, but effects on oxytocin neurons have been previously unexplored. Here we investigated the effects of tuberomammillary nucleus electrical stimulation as well as of histamine antagonists on supraoptic nucleus oxytocin and vasopressin neurons in slices of rat hypothalamus. Electrical stimulation evoked short constant latency (~5ms), fast (4–6 ms onset to peak) inhibitory postsynaptic potentials in oxytocin neurons and, as shown previously, fast excitatory postsynaptic potentials in vasopressin neurons. These synaptic responses followed paired-pulse stimulus frequencies up to 100 Hz and were, thus, probably reflecting monosynaptic connections. Inhibitory postsynaptic potentials were selectively blocked by histamine receptor subtype 2 antagonists (either cimetidine or famotidine) and by picrotoxin but not by histamine receptor subtype 1 antagonists or bicuculline. Similar synaptic responses to tuberomammillary nucleus stimulation were found in 16 of 16 neurons immunocytochemically identified as oxytocinergic and in seven putative oxytocin neurons. Perifusion of the slice with low chloride medium (4.8 mM) reversed stimulus-evoked inhibitory postsynaptic potentials. We conclude that histaminergic neurons monosynaptically contact both oxytocin and vasopressin cells of the supraoptic nucleus and inhibit the former via activation of chloride channels which can be blocked by the histamine receptor subtype 2 antagonists, famotidine and cimetidine.

Effects of an intraperitonially (i.p.) administered histamine H2-receptor antagonist, ranitidine, on plasma levels of vasopressin and oxytocin were studied in male rats under unstressed or stressed conditions. In the rats injected i.p. with the vehicle (saline) solution, plasma vasopressin level was significantly lower and plasma oxytocin level was significantly higher after weak electric foot shocks (10 ms pulses of 0.8 mA, 50 Hz and 1 s duration, repeated at 30 s intervals for a period of 5 min) than those levels in the unshocked control rats. Ranitidine injected i.p. at a dose of 100 mg per kg body weight blocked the suppressive vasopressin but not the facilitatory oxytocin response to the shocks. Novel environmental stimuli were applied to rats in such a way that the animals were transferred to an experimental room, placed in a white-painted plastic pail and administered an intermittent 2 kHz and 70 dB pure tone of 2 s duration that was repeated at 10 s intervals for 2 min. In the rats injected i.p. with the vehicle solution, plasma vasopressin level was lower and oxytocin level was higher after the novel stimuli than in the unstimulated control rats. Ranitidine injected i.p. at a dose of 100 mg per kg body weight blocked the suppressive vasopressin but not the facilitatory oxytocin response to the novel stimuli. Ranitidine administered i.p. at doses of 10, 20, 50 and 100 mg per kg body weight was tested for the suppressive vasopressin response to the novel stimuli given for periods of 2 or 5 min. Ranitidine dose of 100 mg per kg was effective for blocking the suppressive vasopressin response to the novel stimuli. The facilitatory oxytocin response was not clear before ranitidine but became apparent after administration of the drug. The experiments with novel stimuli of 2, 5, 10 or 20 min duration in the vehicle-injected control rats confirmed our previous observations in that a decrease in plasma vasopressin level after the novel stimuli terminated within 10 min even though the stimuli continued, and in that the plasma oxytocin level was not significantly altered by the stimuli. Ranitidine administered i.p. at a dose of 100 mg per kg blocked the suppressive vasopressin response to novel environmental stimuli and made a facilitatory oxytocin response appear. Ranitidine increased the basal plasma level of vasopressin in a dose-related manner. These results suggest that histamine H2 receptors in the brain mediate the suppressive vasopressin response to novelty stress and prevent, in an activity-dependent manner, the facilitatory oxytocin response. They also suggest that histamine H2 receptors are inhibiting vasopressin secretion by the pituitary in a tonic fashion.