Metoprine, a histamine N-methyltransferase inhibitor, attenuates methamphetamine-induced hyperlocomotion via activation of histaminergic neurotransmission in mice.

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.

Cardiac and regional haemodynamic effects of histamine N-methyltransferase inhibitor metoprine in haemorrhage-shocked rats.

OBJECTIVE AND DESIGN: 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. MATERIAL: Cardiovascular parameters were measured in 72 and central histamine concentrations in 12 male Wistar rats anaesthetised with ketamine/xylazine. TREATMENT: 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. METHODS: 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. 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). CONCLUSIONS: The results support the hypothesis that histaminergic system activation leads to mobilisation of compensatory mechanisms in haemorrhagic hypotension.

Involvement of the renin-angiotensin system in endogenous central histamine-induced reversal of critical haemorrhagic hypotension in rats.

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.

Effect of modified brain histamine contents on prolactin and thyrotropin secretion in male rats.

Effects of modified brain histamine contents on thyrotropin and prolactin secretion were studied in male rats. Under basal conditions the histamine content in the hypothalamus was approximately 8-10-fold higher than that in the striatum and the rest of the brain. L-histidine (1000 mg/kg, ip), a histamine precursor, and metoprine (20 mg/kg, ip), an inhibitor of histamine methyltransferase, elevated histamine content in the brain by 65% and 167%, respectively. When the treatments were given together an additive effect (119-250% increase) on brain histamine was observed. Metoprine significantly decreased serum prolactin levels, while L-histidine had no effect. This effect of metoprine was not modified by treatment with L-histidine. Thus, metoprine has an inhibitory effect on prolactin secretion that is not related to elevated brain histamine contents. The increased brain histamine content after L-histidine treatment had no effect on prolactin secretion. Basal levels of serum thyrotropin were decreased by both L-histidine and metoprine, L-histidine being more potent. In rats treated with alpha-fluoromethylhistidine, an inhibitor of L-histidine decarboxylase, the cold-induced (rats kept for 60 min at +4 degrees C) thyrotropin secretion was increased while the stress-induced prolactin secretion was decreased. In these rats, metoprine did not affect thyrotropin release but blunted the prolactin response. In conclusion, endogenous histamine inhibits thyrotropin secretion but does not affect prolactin release. Owing to its other effects, metoprine is not suitable as a tool to elevate endogenous histamine contents in the brain, at least when the regulation of anterior pituitary hormone release is being studied.

Effects of histamine on 5-hydroxytryptaminergic neuronal activity in the rat hypothalamus.

Effects of pharmacological manipulations which mimic or enhance histaminergic neuronal transmission were determined on the activity of 5-hydroxytryptaminergic neurons projecting to the hypothalamus of male rats. Intracerebroventricular administration of histamine decreased 5-hydroxytryptamine (5-HT) and increased 5-hydroxyindoleacetic acid (5-HIAA) concentrations in several hypothalamic nuclei; these effects were blocked by the histamine H1 receptor antagonist mepyramine but not the histamine H2 receptor antagonist zolantidine. Blockade of the 5-HT reuptake system by fluoxetine did not prevent histamine-induced decreases in 5-HT concentrations suggesting that histamine is not transported into nerve terminals via the 5-HT reuptake system to subsequently displace 5-HT stores. These data suggest that exogenous histamine increases 5-hydroxytryptaminergic neuronal activity through an action at histamine H1 receptors. In contrast, neither the histamine H3 receptor antagonist thioperamide, the histamine-N-methyltransferase inhibitor metoprine, nor combined thioperamide-metoprine treatment affected concentrations of 5-HT or 5-HIAA suggesting these agents, which purportedly enhance endogenous histaminergic transmission, do not affect 5-hydroxytryptaminergic neuronal activity. These results reveal that procedures commonly employed to study central actions of histamine differentially affect 5-hydroxytryptaminergic neuronal activity in the rat hypothalamus.

Changes in the rat brain histamine content following metoprine and other histamine-methyltransferase (HMT) inhibitors.

Four compounds: amodiaquine, quinacrine, 1,4-(tele)-methylhistamine and metoprine, which in vitro effectively inhibit histamine N-methyltransferase (HMT) activity, were tested for their effects on histamine (HI) levels in the rat brain and ex vivo HMT activity. In in vitro studies all these compounds at concentration of 10 microM produced complete inhibition of HMT activity. Amodiaquine, quinacrine and 1,4-(tele)-methyl-HI weakly inhibited HMT activity ex vivo and they failed to alter HI levels in the rat brain. Of the tested compounds only metoprine significantly increased brain HI levels in both normal rats and 1-histidine treated rats. Metoprine and, to much lesser degree, amodiaquine, but not aminoguanidine, slowed down the disappearance of exogenous HI from the rat brain. It is suggested that metoprine, because of its simultaneous capability of inhibiting HMT activity and increasing brain HI level, might be a useful pharmacological tool in studies of HI metabolism and neurotransmission in the central nervous system.

The effect of intrahypothalamic injection of homodimaprit on blood pressure.

Bilateral injection of the inhibitor of histamine-N-methyltransferase, SKF 91488, which is also known as homodimaprit (5 micrograms), into the preoptic area of the rat produced delayed hypertension, tachycardia and hyperthermia. Some animals exhibited pulmonary edema. These effects were only noted 18-24 hr after an injection and were not an artifact of the injection, since the administration of artificial cerebrospinal fluid produced none of these effects. At the time noted, lesions of the rostral hypothalamus, including the preoptic area, were evident. Injection of a vasopressin antagonist, intravenously, did not lower the blood pressure of the hypertensive animals nor did previous bilateral adrenal demullation prevent or delay the hypertension or tachycardia. Therefore, it does not appear that hypersecretion of either vasopressin or adrenal catecholamines contributed to the cardiovascular effects. Peripheral pretreatment with the sympathetic neurotoxin 6-hydroxydopamine however, did prevent the delayed rise in blood pressure following an injection of homodimaprit. From these studies, it is concluded that the injection of homodimaprit produces lesions in the preoptic area, resulting in hypertension that is maintained by excessive activation of the sympathetic nervous system.

Biochemical and chemotherapeutic studies on 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine (BW 301U), a novel lipid-soluble inhibitor of dihydrofolate reductase.

The lipophilic diaminopyridopyrimidine BW 301U (2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine) is as active as methotrexate as an inhibitor of dihydrofolate reductase and mammalian cell growth. This compound was selected from among related pyridopyrimidines and other lipid-soluble diaminoheterocyclic compounds as having the most favorable combination of properties as a potent inhibitor of dihydrofolate reductase with minimal effects on histamine metabolism. In contrast to methotrexate, entry of BW 301U into cells is rapid and is not temperature dependent, indicating passage across cell membranes by diffusion. There is no competition between BW 301U and leucovorin (folinic acid) for uptake into Sarcoma 180 cells in culture. When BW 301U is added to culture medium, deoxyuridine incorporation ceases within the first few min, and this inhibition persists when cells are transferred to drug-free medium. Both leucovorin and thymidine are required to protect cells in culture from the cytotoxicity of BW 301U. The effect on thymidine biosynthesis appears to be indirect since BW 301U is inactive as an inhibitor of thymidylate synthetase. Hypoxanthine and thymidine restore growth by only 50% in cultures containing BW 301U, and complete restoration of growth requires the further addition of adenosine and either uridine or cytidine to the medium. In vivo, BW 301U is active against Walker 256, L1210, P388, Sarcoma 180, and Ehrlich ascites tumors.