Kenji Onodera

Effect of thioperamide, a histamine H3 receptor antagonist, on electrically induced convulsions in mice

The effect of thioperamide, a histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Thioperamide significantly and dose dependently decreased the duration of each phase of convulsion and raised the electroconvulsive threshold. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine, a histamine H3 receptor agonist. These findings suggest that the effect of thioperamide on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, an effect mediated by histamine H3 receptors. The anticonvulsant effect of thioperamide was antagonized strongly by mepyramine (or pyrilamine), a centrally acting histamine H1 receptor antagonist, but not by zolantidine, a centrally acting histamine H2 receptor antagonist. Thus, the blockade by mepyramine of the thioperamide-induced decrease in seizure susceptibility indicates that histamine released by thioperamide from the histaminergic nerve terminals interacts with the histamine H1 receptors of postsynaptic neurons. These findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures.

Histamine levels and clonic convulsions of electrically-induced seizure in mice: the effects of α-fluoromethylhistidine and metoprine

SummaryThe purpose of this study was to investigate the possible role of the central histaminergic neuron system in electrically-induced seizure in mice. For this purpose, we examined the effects of intraperitoneal (i. p.) injections of histaminergic agents, such as l-histidine, metoprine, and α-fluoromethylhistidine (FMH), on electrically-induced seizure. l-Histidine decreased the duration of clonic convulsion in electrically-induced seizure, but not affected that of tonic convulsion. This effect of l-histidine was antagonized by pretreatment with FMH, indicating that it was due to histamine formed by decarboxylation of l-histidine in the central nervous system. The anticonvulsive effect of l-histidine was also reduced by the H1-antagonist pyrilamine, but not by the H2-antagonist zolantidine, indicating that the effect on electrically-induced seizure is mediated through central H1-receptors. Metoprine, which increased the histamine levels in the cerebral cortex, diencephalon and midbrain of mice, decreased the duration of clonic convulsions dose-dependently. Conversely, FMH, which decreased the brain histamine levels, increased the duration of clonic convulsions. Good inverse correlations were found between the duration of clonic convulsions and brain histamine levels, especially in the diencephalon: the histamine levels were inversely proportional to the duration of clonic convulsions. No correlation was found between the duration of tonic convulsions and brain histamine levels. These results suggest that the histaminergic neuron system is important in inhibition of the duration of clonic convulsion on electrically induced seizure in mice.

Effects of thioperamide, a histamine H3-receptor antagonist, on a scopolamine-induced learning deficit using an elevated plus-maze test in mice

We examined the effects of thioperamide and (R)-alpha-methylhistamine, a histamine H3-receptor antagonist and an agonist, respectively, on a scopolamine-induced learning deficit using an elevated plus-maze test in mice. Thioperamide alone slightly improved the learning deficit induced by scopolamine, and pretreatment with zolantidine, a histamine H2-receptor antagonist, significantly enhanced the effect of thioperamide in this test. (R)-alpha-Methylhistamine, pyrilamine, ketotifen, terfenadine, and zolantidine alone at the doses tested had no effect. Moreover, the improvement by thioperamide plus zolantidine was antagonized by pretreatment with histamine H1-receptor antagonists such as pyrilamine or ketotifen, but not by terfenadine. Thus, thioperamide improved the scopolamine-induced learning deficit through central histamine H1 receptors in mice. The present results supported the hypothesis that histamine may play an important role in learning and memory.

Effects of the histaminergic system on the morphine-induced conditioned place preference in mice

The effects of an H2 receptor antagonist, a histidine decarboxylase inhibitor and a histamine precursor on the morphine-induced place preference in mice were examined. Morphine (1-7 mg/kg) produced a place preference in a dose-dependent manner. This morphine-induced place preference was significantly antagonized by the dopamine (DA) D1 receptor antagonist SCH 23390. The histamine precursor, L-histidine, attenuated the morphine (7 mg/kg)-induced place preference. On the other hand, the histidine decarboxylase inhibitor, alpha-fluoromethylhistidine (alpha-FMH), significantly potentiated the morphine (1 mg/kg)-induced place preference. This potentiation was antagonized by SCH 23390. The H2 receptor antagonist zolantidine (0.3 mg/kg) significantly potentiated the morphine-induced place preference. Surprisingly, zolantidine (1 mg/kg) alone also produced a significant place preference. The zolantidine-induced place preference was antagonized by SCH 23390. In addition, zolantidine (1, 3 and 10 mg/kg) significantly increased DA turnover (DA ratio) in the limbic forebrain (nucleus accumbens and olfactory tubercle), implying that zolantidine may activate the mesolimbic DA system. Moreover, co-administration of zolantidine dose-dependently increased morphine (10 mg/kg)-induced DA turnover in the limbic forebrain. These results suggest that the activation of histaminergic neurons may attenuate the rewarding effect of morphine, while the inhibition of histaminergic neurons may potentiate the rewarding effect of morphine. Furthermore, potentiation of the morphine-induced rewarding effect by inhibition of histaminergic neurons may be mediated by D1 receptors. We also demonstrated that the H2 receptor antagonist zolantidine may activate the mesolimbic DA system, and as a result, zolantidine itself produces a rewarding effect and potentiates the morphine-induced rewarding effect.

Effects of thioperamide, a histamine H3 receptor antagonist, on locomotor activity and brain histamine content in mast cell-deficient W/Wv mice.

The purpose of this study was to examine the effects of thioperamide, a histamine H3 antagonist, on the locomotor activity and the brain histamine content in mast-cell-deficient W/Wv mice. Thioperamide (12.5 and 25 mg/kg) showed significant increase in the locomotor activity of W/Wv mice, measured by a photo-beam system, 1 hr after the intraperitoneal injection. However, more than 75 mg/kg of thioperamide showed not only the reduction of the locomotor activity but also the inhibition of motor coordination measured by the rotarod performance. The increase in the locomotor activity by thioperamide was blocked by i. p. pretreatment with (R)-alpha-methyl-histamine, an H3 agonist, or pyrilamine, an H1 antagonist, or zolantidine, an H2 antagonist. The brain histamine content was decreased by thioperamide (12.5-75.0 mg/kg), 1 hr after administration. Thus, the blockade of histamine H3 receptor by thioperamide showed the activation of locomotor activity of mice, which may be mediated by H1 and/or H2 receptors. The present data support the hypothesis that central histaminergic neurons may be involved in the control of state of wakefulness.

Improvement by FUB 181, a novel histamine H3-receptor antagonist, of learning and memory in the elevated plus-maze test in mice

Effects of FUB 181 [3-(4-chlorophenyl)propyl-3-(1H-imidazol-4-yl)propyl ether], a novel histamine H3-receptor antagonist, on a scopolamine-induced learning deficit in the elevated plus-maze test were studied in mice. FUB 181 alone (2.5 and 5 mg/kg, i.p.) ameliorated the scopolamine-induced learning deficit in mice. This effect was antagonized by BP 2.94 (10 mg/kg, i.p.), a prodrug of (R)-—methylhistamine (histamine H3-receptor agonist), and by ketotifen (4 mg/kg, i.p.), a histamine H1-receptor antagonist, both penetrating the blood-brain barrier. However, the ameliorating effect of FUB 181 (2.5 mg/kg) was not antagonized by either terfenadine (10 mg/kg, i.p.), a histamine H1-receptor antagonist with poor penetration of the blood-brain barrier, or zolantidine (20 mg/kg, i.p.), a centrally effective histamine H2-receptor antagonist. In a biochemical study, FUB 181 had no significant effect on either acetylcholine or choline level in mice brain at the doses tested. These findings suggest that FUB 181 increases the release of histamine by blocking presynaptic histamine H3 autoreceptors, and that released histamine in turn activates postsynaptic H1 and H2 receptors, predominantly histamine H1 receptors, and in this fashion improves learning and memory in mice. Our findings also suggest that the histaminergic system may play an important role in learning and memory, and that FUB 181 may be a clinical candidate for the therapy of dementia.

Clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, inhibits electrically induced convulsions in mice

The effect of clobenpropit (VUF-9153), a new histamine H3 receptor antagonist, on electrically induced convulsions was studied in mice. Clobenpropit significantly and dose dependently decreased the duration of each convulsive phase. Its anticonvulsant effects were prevented by pretreatment with (R)-alpha-methylhistamine and imetit (VUF-8325), histamine H3 receptor agonists. These findings suggest that the effect of clobenpropit on electrically induced convulsions is due to an increase in endogenous histamine release in the brain, which is consistent with biochemical results that clobenpropit increased brain histidine decarboxylase activity dose dependently. The anticonvulsive effect of clobenpropit was antagonized by mepyramine, a histamine H1 receptor antagonist, but not by zolantidine, a histamine H2 receptor antagonist, indicating that histamine released by the anticonvulsant effect of clobenpropit interacts with histamine H1 receptors of postsynaptic neurons. The present findings of the effect of clobenpropit on electrically induced convulsions are fully consistent with those of thioperamide as described previously (Yokoyama et al., 1993, Eur. J. Pharmacol. 234, 129), supporting the hypothesis that the central histaminergic neuron system is involved in the inhibition of seizures.

The behavioral and biochemical effects of thioperamide, a histamine H3-receptor antagonist, in a light/dark test measuring anxiety in mice

We investigated the effects of thioperamide, a histamine H3-receptor antagonist, in a light/dark test measuring anxiety in mice. Thioperamide (20 mg/kg) slightly affected the locomotion and time spent in a light zone, and shuttle crossing. However, the decreases of these parameters were significant only when the animals were pretreated with zolantidine, a histamine H2-receptor antagonist. Moreover, the decreased parameters induced by the combination of thioperamide and zolantidine were reversed by pretreatment with pyrilamine, a histamine H1-receptor antagonist. These data suggest that thioperamide induces the release of neuronal histamine, which in turn stimulates both H1- and H2-receptors to produce the anxiogenic effect. The stimulation of histamine H1-receptors may mediate the anxiety, while H2-receptors may play a role in masking the anxiogenic effect. Thus, the present study suggests the involvement of endogenous neuronal brain histamine in anxiety. In the biochemical study, a previous report showed that thioperamide accelerated the release of neuronal histamine in the brains of mice [Sakai et al., Life Sciences, 48, 2397-2404(1991)]. This study also demonstrated that thioperamide did not affect the turnover rate of noradrenaline, dopamine, or serotonin in the brains of mice, which indicates that thioperamide is a good pharmacological tool for accelerating the release of neuronal histamine in the brain.

Effects of clobenpropit (VUF-9153), a histamine H3-receptor antagonist, on learning and memory, and on cholinergic and monoaminergic systems in mice.

The effects of clobenpropit (VUF-9153), a potent histamine H3-receptor antagonist, on a scopolamine-induced learning deficit in the step-through passive avoidance test was studied in mice. Clobenpropit (10 and 20 mg/kg) alone showed a tendency to ameliorate the scopolamine-induced learning deficit, and clobenpropit (10 mg/kg) in combination with zolantidine (20 mg/kg), a histamine H2-receptor antagonist, ameliorated the scopolamine-induced effect. This ameliorating effect was antagonized by (R)-alpha-methylhistamine (20 mg/kg), a histamine H3-receptor agonist and pyrilamine (20 mg/kg), a histamine H1-receptor antagonist, suggesting that clobenpropit in combination with zolantidine showed the ameliorating effect via histamine H3 receptors and/or histamine H1 receptors. We also studied the effects of clobenpropit on cholinergic and monoaminergic systems. Clobenpropit did not show any significant effect on these neuronal systems except the activation of noradrenergic system. The present results suggest that the effect of clobenpropit might be partially involved with the activation of noradrenergic system, and the histaminergic system may play certain important roles in learning and memory.

Ameliorating effects of histidine on scopolamine-induced learning deficits using an elevated plus-maze test in mice

We investigated the effects of histidine on scopolamine-induced learning deficits in the elevated plus-maze test in mice. In this test, transfer latency (TL), the time mice took to move from the open arm to the enclosed arm, was used as an index of learning and memory. Intraperitoneal administration of scopolamine (0.5 mg/kg) prolonged the TL on day 2 compared with that in the saline-treated group. Histidine loading (500, 800 and 1600 mg/kg) reversed the prolongation of the TL induced by scopolamine. This ameliorating effect of histidine was abolished by alpha-fluoromethylhistidine, an inhibitor of histidine decarboxylase, suggesting that histidine itself has no such ameliorating effect. Moreover, the ameliorating effect of histidine was antagonized by a histamine H1 receptor antagonist, pyrilamine. However, zolantidine, a histamine H2 receptor antagonist, showed no antagonism of the effect of histidine. Thus, histamine, a decarboxylated product of histidine, elicited an ameliorating effect on scopolamine-induced learning deficit via histamine H1 receptors in mice. These findings clearly indicated that there is a close relationship between histaminergic and cholinergic systems in the brain, and that histamine may play certain important roles in learning and memory.