Abstract Explosive running is a reliable initial component of audiogenic seizures (AS) induced by acoustic stimulation in genetically prone rodents. This profound locomotor activation is usually ...considered as a convulsive manifestation of AS although some studies attribute running to a panic-like response. Increase in central histamine activity has been shown to suppress clonic and tonic seizures. The present study examined the involvement of histaminergic mechanisms in the expression of running component of AS. Metoprine, an inhibitor of histamine- N -methyltransferase, was used to increase brain histamine level. Running was induced 4 and 24 h after intraperitoneal injection of metoprine or vehicle in rats of different strains. A brief sound stimulation elicited running followed by clonic–tonic convulsions in Krushinsky–Molodkina (KM) rats or running alone in AS-prone Wistar and WAG/Rij rats. In KM rats, metoprine exerted opposite effects on the main phases of AS. It increased the duration of running and decreased the duration and severity of clonic–tonic convulsions. In Wistar rats, metoprine produced a remarkable aggravation of running leading to its 2- to 3-fold prolongation. In WAG/Rij rats with mixed seizures (absence and audiogenic), the drug caused either aggravation or suppression of running behavior. These results suggest specific role for histaminergic system in the expression of behavioral components of AS. Suppressive role of histamine in clonic–tonic seizures is associated with facilitation of running suggesting specific effects of histamine on brainstem neuronal networks underlying these phases of AS. Possible roles of histaminergic mechanisms in seizure, motor and aversive aspects of sound-induced running are discussed.
The effects of α-fluoromethylhistidine (α-FMH) on spatial cognition were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (ICV) injection of α-FMH resulted in ...spatial memory deficits characterized by an increase in the number of total errors (TE) and a decrease in the number of initial correct responses (ICR). There was a strong correlation between increases in the number of TE and decreases in histamine contents of the cortex and hippocampus regions of the brain, which are known to participate in learning and memory. On the other hand, both histamine (50–100 ng, ICV) and thioperamide (10 μg, ICV) significantly ameliorated the memory deficit induced by α-FMH. However, metoprine showed no significant effect on the α-FMH–induced memory deficit. Pyrilamine and R-(α)-methylhistamine enhanced the memory deficit induced by α-FMH, at doses that had no appreciable effect when administered alone. In contrast, no significant influence on α-FMH–induced memory deficit was observed with zolantidine.
The present study was undertaken to clarify the role of histaminergic neuron system on amygdaloid kindled seizures in rats. A significant decrease in histamine contents in the amygdala was observed ...after development of amygdaloid kindling. Histidine and metoprine inhibited amygdaloid kindled seizures at doses causing an increase in histamine contents of the brain. H
1-antagonists (diphenhydramine and chlorpheniramine) attenuated histidine-induced inhibition of amygdaloid kindled seizures, however no significant antagonism was observed with H
2-antagonists (zolantidine and ranitidine). The development of amygdaloid kindling was retarded by repeated administration of histidine. These findings suggest that histaminergic mechanisms play a suppressive role in amygdaloid kindled seizures through histamine H
1-receptors.
The aim of this study was to elucidate the effect caused by the inhibition of histamine catabolism by means of metoprine and the activation of histamine H
1 receptors by selective agonists on ...learning and memory processes, using a modified method of the mouse passive avoidance test. The administration of scopolamine 1 mg/kg (i.p.) immediately after the training session caused statistically-significant amnesia during the retention trial performed 24 h later. Piracetam (30 mg/kg (i.p.)), used as a positive control, and administered 20 min before the training session, prevented scopolamine-induced memory impairment. The histamine-
N-methyltransferase inhibitor, metoprine, (2 and 5 mg/kg (s.c.)) had effects similar to those of this nootropic drug. The highly-selective H
1 receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 μg/mouse (i.c.v.)) and the less selective agonist, 2-thiazolylethylamine (2-TEA) (0.1 and 0.3 μg/mouse (i.c.v.)) both antagonized the scopolamine-induced amnesia significantly and in a dose-related manner. The selective H
1 receptor antagonist, pyrilamine (20 mg/kg (i.p.)), revealed no effect by itself, but significantly prevented the antiamnesic action both that of the H
1 receptor agonists, and that of endogenous histamine, released by metoprine, thus suggesting a cognitive improvement via the activation of H
1 receptors.
Metoprine elevates brain histamine content by blocking the conversion of histamine to methylhistamine. It suppresses food intake, increases water intake, and induces diuresis in rats. In the present ...experiment, to study which receptors were involved in these metoprine-induced changes, H
1, H
2, and H
3 receptor blockers were administered to metoprine (10 mg/kg IP)-treated rats. The food and water consumption and urine excretion were measured at 10 and 24 h after the drug administration. It was found that systemic administration of the H
3 receptor antagonist, thioperamide (5 mg/kg IP), supplemented the feeding suppressive effect of metoprine. In addition to this, the H
1 receptor antagonist mepyramine (20 mg/kg IP) antagonized the suppression of feeding in metoprine-treated rats, whereas the H
2 receptor antagonist, ranitidine (100 mg/kg IP), had no effect. Mepyramine also decreased the diuretic response to metoprine, whereas ranitidine or thioperamide were virtually without effect. The present results show that elevation of brain histamine content by inhibiting the catabolism of histamine suppresses food intake, and this effect of metoprine can be abolished by pretreatment with antihistamines. Although the blockade of H
1 receptors also attenuates the diuretic response to metoprine, further studies are needed to understand the mechanisms that mediate the effects of metoprine on water balance.
Role of histamine in rodent antinociception Malmberg‐Aiello, Petra; Lamberti, Claudia; Ghelardini, Carla ...
British journal of pharmacology,
April 1994, Volume:
111, Issue:
4
Journal Article
Peer reviewed
Open access
1
Effects of substances which are able to alter brain histamine levels on the nociceptive threshold were investigated in mice and rats by means of tests inducing three different kinds of noxious ...stimuli: mechanical (paw pressure), chemical (abdominal constriction) and thermal (hot plate).
2
A wide range of i.c.v. doses of histamine 2HCl was studied. Relatively high doses were dose‐dependently antinociceptive in all three tests: 5–100 μg per rat in the paw pressure test, 5–50 μg per mouse in the abdominal constriction test and 50–100 μg per mouse in the hot plate test. Conversely, very low doses were hyperalgesic: 0.5 μg per rat in the paw pressure test and 0.1–1 μg per mouse in the hot plate test. In the abdominal constriction test no hyperalgesic effect was observed.
3
The histamine H3 antagonist, thioperamide maleate, elicited a weak but statistically significant dose‐dependent antinociceptive effect by both parenteral (10–40 mg kg−1) and i.c.v. (1.1–10 μg per rat and 3.4–10 μg per mouse) routes.
4
The histamine H3 agonist, (R)‐α‐methylhistamine dihydrogenomaleate was hyperalgesic, with a rapid effect (15 min after treatment) following i.c.v. administration of 1 μg per rat and 3 μg per mouse, or i.p. administration of 100 mg kg−1in mice. In rats 20 mg kg−1, i.p., elicited hyperalgesia only 4 h after treatment.
5
Thioperamide‐induced antinociception was completely prevented by pretreatment with a non‐hyperalgesic i.p. dose of (R)‐α‐methylhistamine in the mouse hot plate and abdominal constriction tests. Antagonism was also observed when both substances were administered i.c.v. in rats.
6
l‐Histidine HCl dose‐dependently induced a slowly occurring antinociception in all three tests. The doses of 250 and 500 mg kg−1, i.p. were effective in the rat paw pressure test, and those of 500 and 1500 mg kg−1, i.p. in the mouse hot plate test. In the mouse abdominal constriction test 500 and 1000 mg kg−1, i.p. showed their maximum effect 2 h after treatment.
7
The histamine N‐methyltransferase inhibitor, metoprine, elicited a long‐lasting, dose‐dependent antinociception in all three tests by both i.p. (10–30 mg kg−1) and i.c.v. (50–100 μg per rat) routes.
8
To ascertain the mechanism of action of the antinociceptive effect of l‐histidine and metoprine, the two substances were also studied in combination with the histamine synthesis inhibitor (S)‐α‐fluoro‐methylhistidine and with (R)‐α‐methylhistamine, respectively. l‐Histidine antinociception was completely antagonized in all three tests by pretreatment with (S)‐α‐fluoromethylhistidine HCl (50 mg kg−1, i.p.) administered 2 h before l‐histidine treatment. Similarly, metoprine antinociception was prevented by (R)‐α‐methylhistamine dihydrogenomaleate 20 mg kg−1, i.p. administered 15 min before metoprine. Both (S)‐α‐fluoromethylhistidine and (R)‐α‐methylhistamine were used at doses which did not modify the nociceptive threshold when given alone.
9
The catabolism product, 1‐methylhistamine, administered i.c.v. had no effect in either rat paw pressure or mouse abdominal constriction tests.
10
These results indicate that the antinociceptive action of histamine may take place on the postsynaptic site, and that its hyperalgesic effect occurs with low doses acting on the presynaptic receptor. This hypothesis is supported by the fact that the H3 antagonist, thioperamide is antinociceptive and the H3 agonist, (R)‐α‐methylhistamine is hyperalgesic, probably modulating endogenous histamine release. l‐Histidine and metoprine, which are both able to increase brain histamine levels, are also able to induce antinociception in mice and rats. Involvement of the histaminergic system in the modulation of nociceptive stimuli is thus proposed.
Effects of substances which are able to alter brain histamine levels and two histamine H1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test.
...Imipramine (10 and 30 mg kg−1, i.p.) and amitriptyline (5 and 15 mg kg−1, i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H3 receptor agonist, (R)‐α‐methylhistamine, at a dose (10 mg kg−1, i.p.) which did not modify the cumulative time of immobility.
The histamine H3 receptor antagonist, thioperamide (2–20 mg kg−1, s.c.), showed an antidepressant‐like effect, with a maximum at the dose of 5 mg kg−1, which was completely prevented by (R)‐α‐methylhistamine.
The histamine‐N‐methyltransferase inhibitor, metoprine (2–20 mg kg−1, s.c.), was effective with an ED50 of 4.02 (2.71–5.96) mg kg−1; its effect was prevented by (R)‐α‐methylhistamine.
The histamine precursor, l‐histidine (100–1000 mg kg−1, i.p.), dose‐dependently decreased the time of immobility ED30 587 (499–712) mg kg−1. The effect of 500 mg kg−1 l‐histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)‐α‐fluoromethylhistidine (50 mg kg−1, i.p.), administered 15 h before.
The highly selective histamine H1 receptor agonist, 2‐(3‐trifluoromethylphenyl)histamine (0.3–6.5 μg per mouse, i.c.v.), and the better known H1 agonist, 2‐thiazolylethylamine (0.1–1 μg per mouse, i.c.v.), were both dose‐dependently effective in decreasing the time of immobility ED50 3.6 (1.53–8.48) and 1.34 (0.084–21.5) μg per mouse, respectively.
None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test.
It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant‐like effect, via activation of H1 receptors.
British Journal of Pharmacology (1998) 123, 1331–1336; doi:10.1038/sj.bjp.0701740
The study was undertaken to examine the involvement of the renin-angiotensin system in the reversal by endogenous central histamine of critical haemorrhagic hypotension in anaesthetised Wistar rats. ...Histamine N-methyltransferase inhibitor metoprine (20 microg) administered intracerebroventricularly at 5 min of critical hypotension 20-25 mmHg produced increases in histamine concentrations as measured 20 min after treatment in the hypothalamus (581.33 +/- 63.23 vs. 488.26 +/- 56.34 ng/g of wet tissue; P < 0.01) and medulla oblongata (53.42 +/- 14.65 vs. 34.68 +/- 13.52 ng/g of wet tissue; P < 0.05). That was accompanied by 34.7% higher plasma angiotensin II concentration in comparison to the control group. Metoprine produced dose-dependent (5-20 microg) rises in mean arterial pressure (MAP) and heart rate, which were significantly higher than those in normotensive animals. The resuscitating action of metoprine (20 microg) was associated with rises in renal, mesenteric and hindquarters blood flows, and a 100% survival at 2 h after treatment, while in the saline-treated group, all the animals died within 30 min. Angiotensin type 1 (AT(1)) receptor antagonist ZD 7155 (0.5 mg/kg; iv) decreased regional vascular resistance and inhibited metoprine-induced increase in MAP, whereas AT(2) receptor blocker PD 123319 (10 mg/kg; i.v.) had no effect. Angiotensin-converting enzyme inhibitor captopril (30 mg/kg; i.v.) reduced the increase in plasma angiotensin II level and the haemodynamic effects of metoprine. Neither capropril, nor angiotensin receptor antagonists influence the survival at 2 h after treatment. In conclusion, the renin-angiotensin system is involved in central histamine-induced resuscitating action in rats.
The increase in central histamine concentrations after inhibition of histamine N-methyltransferase (HNMT) activity is associated with the reversal of critical haemorrhagic hypotension, therefore the ...present study examines cardiac and regional haemodynamic effects of HNMT inhibitor metoprine in haemorrhage-shocked rats.
Cardiovascular parameters were measured in 72 and central histamine concentrations in 12 male Wistar rats anaesthetised with ketamine/xylazine.
Metoprine (5, 15 mg/kg) was administered intraperitoneally to normotensive and critically-hypotensive rats with mean arterial pressure (MAP) 20-25 mmHg. Haemorrhage-shocked rats were pre-treated intracerebroventricularly with histamine H(3) receptor agonist R(-)-alpha-methylhistamine (10 microg) or saline.
MAP, heart rate (HR) and cardiac and regional haemodynamics were monitored within 2 h after treatment, or to death if it occurred earlier. Histamine concentrations were measured using enzyme immunoassay. ANOVA followed by Neuman-Keules test, and Fisher's exact test were used to compare the results.
Bleeding resulted in an extreme decrease in cardiac index (CI), an increase in total peripheral resistance index (TPRI) and the death of control animals within 30 min. Metoprine induced increases in MAP and HR which were significantly higher in hypotensive than in normotensive animals. The resuscitating effect of metoprine (15 mg/kg) was associated with a rise in CI, a decrease in TPRI, and a 100% survival at 2 h. TPRI changes resulted from decreased renal, hindquarters and mesenteric vascular resistance. R(-)-alpha-methylhistamine inhibited metoprine-induced increases in endogenous histamine concentrations in the cerebral cortex (0.89 +/- 0.12 vs. 1.25 +/- 0.29 nmol/g of wet tissue; P < 0.05), hypothalamus (4.37 +/- 0.42 vs. 5.74 +/- 0.47 nmol/g of wet tissue; P < 0.01) and medulla oblongata (0.39 +/- 0.07 vs. 0.65 +/- 0.28 nmol/g of wet tissue; P < 0.05), diminished haemodynamic effects and decreased the survival rate at 2 h to 33% (P < 0.05 vs. the saline-pre-treated group).
The results support the hypothesis that histaminergic system activation leads to mobilisation of compensatory mechanisms in haemorrhagic hypotension.
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