Metoprine increases the content of histamine in brain by inhibiting histamine N-methyltransferase (HMT), a centrally acting histamine degrading enzyme. We present data demonstrating that pretreatment ...with metoprine attenuates the hyperlocomotive effects of METH in mice using a multi-configuration behavior apparatus designed to monitor four behavioral outcomes horizontal locomotion, appetitive behavior (food access), and food and water intake. Metoprine pretreatment itself induced hyperlocomotion in mice challenged with saline during the large part of light phase. The trend was also observed during the following dark phase. This is the first report that metoprine has a long-lasting locomotor stimulating property. Similarly, in a tail suspension test, a single injection of metoprine significantly reduced total time of immobility in mice, consistent with the idea that metoprine possesses motor stimulating properties. Metoprine pretreatment did not affect other aspects of behavior. Metoprine did not affect the appetitive and drinking behavior while exerted an effect on stereotypy. No stereotyped behavior was observed in mice pretreated with vehicle followed by METH, while stereotyped sniffing was observed in mice pretreated with metoprine followed by METH. The metoprine pretreatment attenuated METH-induced hyperlocomotion during the first 2 h of light phase, suggesting that metoprine-induced locomotor stimulating property might be different from that of METH. The hypothalamic content of histamine (but not its brain metabolite) was increased after metoprine or METH administration. Both METH and metoprine reduced dopamine and histamine turnover in the striatum and the nucleus accumbens and the hypothalamus, respectively, and there is a significant metoprine pretreatment x METH challenge interaction in the histamine turnover. It is likely that metoprine may attenuate METH-induced hyperlocomotion via activation of histaminergic neurotransmission. Metoprine also might induce a long-lasting locomotor stimulating effect via a putative mechanism different from that whereby METH induces the locomotor stimulating effect.
•Pretreatment with metoprine attenuates METH-induced hyperlocomotion.•Metoprine pretreatment itself induced hyperlocomotion.•Activation of histamine neurotransmission might exert metoprine effects.
Objective
To evaluate the contribution of endogenous diamine oxidase (DAO) in the inactivation of exogenous histamine, to find a mouse strain with increased histamine sensitivity and to test the ...efficacy of rhDAO in a histamine challenge model.
Methods
Diamine oxidase knockout (KO) mice were challenged with orally and subcutaneously administered histamine in combination with the β-adrenergic blocker propranolol, with the two histamine-
N
-methyltransferase (HNMT) inhibitors metoprine and tacrine, with folic acid to mimic acute kidney injury and treated with recombinant human DAO. Core body temperature was measured using a subcutaneously implanted microchip and histamine plasma levels were quantified using a homogeneous time resolved fluorescence assay.
Results
Core body temperature and plasma histamine levels were not significantly different between wild type (WT) and DAO KO mice after oral and subcutaneous histamine challenge with and without acute kidney injury or administration of HNMT inhibitors. Treatment with recombinant human DAO reduced the mean area under the curve (AUC) for core body temperature loss by 63% (
p
= 0.002) and the clinical score by 88% (
p
< 0.001). The AUC of the histamine concentration was reduced by 81%.
Conclusions
Inactivation of exogenous histamine is not driven by enzymatic degradation and kidney filtration. Treatment with recombinant human DAO strongly reduced histamine-induced core body temperature loss, histamine concentrations and prevented the development of severe clinical symptoms.
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 sub(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 sub(1) receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 mu g/mouse (i.c.v.)) and the less selective agonist, 2-thiazolylethylamine (2-TEA) (0.1 and 0.3 mu g/mouse (i.c.v.)) both antagonized the scopolamine-induced amnesia significantly and in a dose-related manner. The selective H sub(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 sub(1) receptor agonists, and that of endogenous histamine, released by metoprine, thus suggesting a cognitive improvement via the activation of H sub(1) receptors.
The administration of methamphetamine (METH, 10 mg/kg, i.p.) to male ICR mice induced stereotyped behavior consisting of nail and/or wood chip biting (86.0%), continuous sniffing (12.0%), head ...bobbing (1.1%), and circling (1.0%) during the observation period of 1 h. Pretreatment of the mice with metoprine (2, 10, and 20 mg/kg, i.p.), a selective inhibitor of histamine
N-methyltransferase (HMT), which metabolizes histamine in the brain, significantly increased and decreased METH-induced continuous sniffing (20.5, 51.3, and 80.3%) and nail and/or wood chip biting (77.4, 45.3, and 14.2%), respectively, in a dose-dependent manner. The hypothalamic contents of histamine and its metabolite
N
τ-methylhistamine were significantly increased and decreased by metoprine (10 mg/kg, i.p.), respectively. The metoprine action on METH-induced behavior was completely abolished by pyrilamine (10 and 20 mg/kg) and ketotifen (10 mg/kg), selective, centrally acting histamine H
1 receptor antagonists, but not by fexofenadine (20 mg/kg), zolantidine (10 mg/kg) and thioperamide (10 mg/kg), a peripherally acting histamine H
1 receptor antagonist and a selective, brain-penetrating antagonist for histamine H
2 and H
3 receptors, respectively. The metoprine action was mimicked by SKF 91488 (100 μg/animal, i.c.v.), another HMT inhibitor, and the action of SKF 91488 was also blocked by pyrilamine. The frequency of the expression of METH-induced total stereotypic patterns was unchanged after metoprine pretreatment. Mice pretreated with metoprine displayed no anxiety-like behavior in the elevated plus maze test. These results suggest that brain histamine, increased by agents such as metoprine and SKF 91488, binds to histamine H
1 receptors in the brain, resulting in the modulation of dopaminergic transmission associated with stereotyped behavioral patterns induced by METH.
Stereotypical behaviors induced by methamphetamine (METH) overdose are one of the overt symptoms of METH abuse, which can be easily assessed in animal models. Currently, there is no successful ...treatment for METH overdose. There is increasing evidence that elevated levels of brain histamine can attenuate METH-induced behavioral abnormalities, which might therefore constitute a novel therapeutic treatment for METH abuse and METH overdose. In mammals, histamine N-methyltransferase (HMT) is the sole enzyme responsible for degrading histamine in the brain. Metoprine, one of the most potent HMT inhibitors, can cross the blood-brain barrier and increase brain histamine levels by inhibiting HMT. Consequently, this compound can be a candidate for a prototype of drugs for the treatment of METH overdose.
In mammals, histamine action is terminated through metabolic inactivation by histamine N-methyltransferase (HNMT) and diamine oxidase. In addition to three well-studied pharmacological functions, ...smooth muscle contraction, increased vascular permeability, and stimulation of gastric acid secretion, histamine plays important roles in neurotransmission, immunomodulation, and regulation of cell proliferation. The histamine receptor H1 antagonist diphenhydramine, the antimalarial drug amodiaquine, the antifolate drug metoprine, and the anticholinesterase drug tacrine (an early drug for Alzheimer's disease) are surprisingly all potent HNMT inhibitors, having inhibition constants in the range of 10–100
nM. We have determined the structural mode of interaction of these four inhibitors with HNMT. Despite their structural diversity, they all occupy the histamine-binding site, thus blocking access to the enzyme's active site. Near the N terminus of HNMT, several aromatic residues (Phe9, Tyr15, and Phe19) adopt different rotamer conformations or become disordered in the enzyme–inhibitor complexes, accommodating the diverse, rigid hydrophobic groups of the inhibitors. The maximized shape complementarity between the protein aromatic side-chains and aromatic ring(s) of the inhibitors are responsible for the tight binding of these varied inhibitors.
Summary The effects of metoprine, an inhibitor of histamine N-methyltransferase, on open field activity and brain regional histamine (HA) content were examined in rats with mixed, absence and ...audiogenic, epilepsy (WAG/Rij-AGS), rats with audiogenic epilepsy (Wistar-AGS) and in non-epileptic control rats (Wistar-nAGS). HA content was increased by metoprine (20 mg/kg, i.p.) in the cortex, striatum, thalamus, hypothalamus and hippocampus of the rats from all three tested groups. However, WAG/Rij rats showed a lower rate of metoprine-induced HA accumulation in the striatum and thalamus than Wistar rats. For the open field test, the main effect of metoprine (20 mg/kg, i.p.) was a general increase of locomotor activity although distinctive features, such as hyperlocomotion and exaggerated sniffing, were characteristic for the epileptic rats (WAG/Rij-AGS and Wistar-AGS, respectively). Individual rats from all the groups showed stereotyped behavior of shuttle type and head bobbing. Electroencephalographic data obtained in WAG/Rij-AGS rats confirmed that metoprine-induced behavioral activation was accompanied by suppression of spike-wave discharges, the main hallmark of absence seizures. Taken together, these results show that inhibition of the histamine catabolism may induce motor activation of particular patterns in epileptic rats and provoke stereotyped behavior.
Abstract The administration of methamphetamine (METH, 10 mg/kg, i.p.) to male ICR mice induced stereotyped behavior consisting of nail and/or wood chip biting (86.0%), continuous sniffing (12.0%), ...head bobbing (1.1%), and circling (1.0%) during the observation period of 1 h. Pretreatment of the mice with metoprine (2, 10, and 20 mg/kg, i.p.), a selective inhibitor of histamine N -methyltransferase (HMT), which metabolizes histamine in the brain, significantly increased and decreased METH-induced continuous sniffing (20.5, 51.3, and 80.3%) and nail and/or wood chip biting (77.4, 45.3, and 14.2%), respectively, in a dose-dependent manner. The hypothalamic contents of histamine and its metabolite Nτ -methylhistamine were significantly increased and decreased by metoprine (10 mg/kg, i.p.), respectively. The metoprine action on METH-induced behavior was completely abolished by pyrilamine (10 and 20 mg/kg) and ketotifen (10 mg/kg), selective, centrally acting histamine H1 receptor antagonists, but not by fexofenadine (20 mg/kg), zolantidine (10 mg/kg) and thioperamide (10 mg/kg), a peripherally acting histamine H1 receptor antagonist and a selective, brain-penetrating antagonist for histamine H2 and H3 receptors, respectively. The metoprine action was mimicked by SKF 91488 (100 μg/animal, i.c.v.), another HMT inhibitor, and the action of SKF 91488 was also blocked by pyrilamine. The frequency of the expression of METH-induced total stereotypic patterns was unchanged after metoprine pretreatment. Mice pretreated with metoprine displayed no anxiety-like behavior in the elevated plus maze test. These results suggest that brain histamine, increased by agents such as metoprine and SKF 91488, binds to histamine H1 receptors in the brain, resulting in the modulation of dopaminergic transmission associated with stereotyped behavioral patterns induced by METH.
Effects of substances that are able to alter the histamine level, a histamine H(1)-receptor agonist and antagonist, and a histamine H(2)-receptor agonist were investigated in an anxiety-like state in ...mice by means of the light/dark box test. Diazepam was used as positive control. The histamine H(3)-receptor antagonist, thioperamide (2, 5, and 20 mg/kg s.c.), showed an anxiogenic-like effect that reached a maximum with the dosage of 5 mg/kg. The histamine-N-methyltransferase (HMT) inhibitor, metoprine (5 and 20 mg/kg s.c.), also decreased the time in the light at the highest dose used and, likewise, the highly selective histamine H(1)-receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 microg/mouse, i.c.v.). On the contrary, the histamine H(2)-receptor agonist, impromidine (3, 10, 20, and 30 microg/mouse, i.c.v.), dose-dependently showed an anxiolytic-like effect. The selective histamine H(1) antagonist, pyrilamine (20 mg/kg i.p.) was able to prevent the anxiogenic-like effect of FMPH significantly, and that of thioperamide partially, while the effect caused by metoprine remained unvaried. It is suggested that the histaminergic system modulates anxiety-like states via the activation of both postsynaptic receptors in a contrasting manner: activation of the H(1) receptor causes an anxiogenic-like effect, while that of the H(2) receptors reduces anxiousness. However, on the basis of effects observed with the substances capable of releasing endogenous histamine, it seems likely that the anxiogenic-like effect is prevalent.
Effects of substances that are able to alter the histamine level, a histamine H
1-receptor agonist and antagonist, and a histamine H
2-receptor agonist were investigated in an anxiety-like state in ...mice by means of the light/dark box test. Diazepam was used as positive control. The histamine H
3-receptor antagonist, thioperamide (2, 5, and 20 mg/kg sc), showed an anxiogenic-like effect that reached a maximum with the dosage of 5 mg/kg. The histamine-
N-methyltransferase (HMT) inhibitor, metoprine (5 and 20 mg/kg sc), also decreased the time in the light at the highest dose used and, likewise, the highly selective histamine H
1-receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 μg/mouse, icv). On the contrary, the histamine H
2-receptor agonist, impromidine (3, 10, 20, and 30 μg/mouse, icv), dose-dependently showed an anxiolytic-like effect. The selective histamine H
1 antagonist, pyrilamine (20 mg/kg ip) was able to prevent the anxiogenic-like effect of FMPH significantly, and that of thioperamide partially, while the effect caused by metoprine remained unvaried. It is suggested that the histaminergic system modulates anxiety-like states via the activation of both postsynaptic receptors in a contrasting manner: activation of the H
1 receptor causes an anxiogenic-like effect, while that of the H
2 receptors reduces anxiousness. However, on the basis of effects observed with the substances capable of releasing endogenous histamine, it seems likely that the anxiogenic-like effect is prevalent.
PDF
