Kenji Ichihara

Effects of haloperidol, sulpiride and SCH 23390 on passive avoidance learning in mice

The main purpose of the present study was to examine the effect of dopamine blockers on memory processes by means of a one-trial passive avoidance (PA) task with ddY mice. Haloperidol (0.025-0.4 mg/kg i.p.) did not affect the PA response when it was given before the training or retention test. Sulpiride (10-80 mg/kg i.p.) had different effects, depending on the doses employed: A lower dose (20 mg/kg) of sulpiride, which is thought to block presynaptic receptors, impaired the PA response but higher doses (40 and 80 mg/kg i.p.) did not affect it when sulpiride was given before the training or retention test. SCH 23390 (0.025-0.1 mg/kg i.p.) impaired the PA response only when it was given before the training. These results suggest that blocking of postsynaptic D-2 receptors does not impair memory processes but blocking of presynaptic D-2 receptors impairs both acquisition and retrieval stages of memory processes following an increase in dopamine release. The involvement of D-1 receptors in memory processes involved in the PA response may be essentially different from that of D-2 receptors, since the blocking of D1 receptors impaired only memory acquisition.

Opposite effects induced by low and high doses of apomorphine on single-trial passive avoidance learning in mice

The effects of apomorphine (0.0125-1 mg/kg, SC), a dopamine (DA) agonist, on passive avoidance learning were assessed in mice which received brief and long foot-shocks in a training test. At low doses, apomorphine stimulates DA autoreceptors. With a shock of brief duration, apomorphine at a low dose (0.05 mg/kg), enhanced the avoidance learning when it was administered 20 min before the training test or the retention test. At high doses, apomorphine stimulates postsynaptic DA receptors. With a shock of long duration, apomorphine at a high dose (1 mg/kg), impaired the avoidance learning when it was administered 20 min before the training test or the retention test. However, apomorphine (0.05 and 1 mg/kg) given immediately after the training test did not have any effect on the avoidance behavior with shocks of either brief or long durations. Apomorphine-induced enhancement of passive avoidance learning was antagonized by sulpiride, but not by haloperidol. These results show that apomorphine induced the opposite effects on the passive avoidance learning depending on the dose or on the reinforcement intensity and suggest that the central DA system may play an important role in modulating memory processes.

Differential effects of pimozide and SCH 23390 on acquisition of learning in mice

Our main purpose was to clarify the differences between the effects of dopamine D-1 (SCH 23390) and D-2 (pimozide) antagonists on memory acquisition in a water-finding and a one-trial passive avoidance task with ddY mice. In the water-finding task, pimozide (0.1 and 0.2 mg/kg i.p.) enhanced the acquisition of latent learning of mice although it suppressed exploratory behavior. In contrast, SCH 23390 (0.1 mg/kg i.p.) attenuated the acquisition of latent learning and suppressed exploratory behavior. In the passive avoidance task, pimozide (0.1 and 0.2 mg/kg i.p.) enhanced the acquisition of the passive avoidance response of mice. SCH 23390 (0.05 and 0.1 mg/kg i.p.) failed to enhance the acquisition of the passive avoidance response. These results could suggest that a moderate block of D-2 receptors enhances memory acquisition but blocking D-1 receptors affects it in an opposite way.

Effects of dopamine receptor agonists on passive avoidance learning in mice : interaction of dopamine D1 and D2 receptors

The present study examined the effects of dopamine D1 and D2 receptor agonists on the acquisition stage of passive avoidance learning and on locomotor activity in mice. The D2 agonist, RU 24213 (1-10 mg/kg s.c.), and the non-selective agonist, apomorphine (0.3-3 mg/kg s.c.), but not the D1 agonist, SKF 38393 (1-10 mg/kg s.c.), impaired learning and activated locomotion. RU 24213 (1 mg/kg s.c.) was more effective in impairing learning than in activating locomotion. The concurrent administration of SKF 38393 (10 mg/kg i.p.) and RU 24213 (1 and 3 mg/kg s.c.) produced a synergistic effect in both behavioral situations. The D1 antagonist, SCH 23390 (0.025 mg/kg i.p.), slightly inhibited the effects of apomorphine and of the combination of SKF 38393 and RU 24213 on learning but not on locomotion. The D2 antagonist, (-)-sulpiride (40 mg/kg i.p.), completely blocked these effects in both situations. These results suggest that dopamine receptor agonists impair passive avoidance learning through the D2 receptor, and that D1 and D2 receptors act synergistically in this impairment, as they do in their effects on locomotion. The involvement of D1 and D2 receptors is qualitatively similar in each of these behaviors, although some small differences may exist.

Effects of nefiracetam on drug-induced impairment of latent learning in mice in a water finding task

We investigated the effects of nefiracetam (DM-9384), a pyrrolidone derivative, on chlordiazepoxide-, apomorphine-, and methamphetamine-induced impairment of latent learning in a water finding test in mice. Pretreatment with nefiracetam reversed the inhibitory effects of chlordiazepoxide and apomorphine, but not those of methamphetamine, on latent learning. The ameliorative effects of nefiracetam on apomorphine-induced, but not chlordiazepoxide-induced impairment of latent learning were antagonized by scopolamine. These results provide further evidence that nefiracetam has anti-amnesic effects. Further, it is suggested that the cholinergic neuronal system may be involved in the ameliorative effects exerted by nefiracetam on apomorphine-induced impairment of latent learning.

Involvement of GABAergic systems in benzodiazepine-induced impairment of passive avoidance learning in mice.

The possible involvement of GABAergic neuronal systems in benzodiazepine(BZP)-induced impairment of a passive avoidance response was investigated. Chlordiazepoxide(CDP) impaired passive avoidance when administered prior to training. The CDP-induced impairment was antagonized by pretreatment with picrotoxin, but not by pretreatment with bicuculline or posttraining administration of picrotoxin. On the contrary, when combined with muscimol, the dose at which CDP impaired the response was lower than the dose at which it did so alone. The synergy of muscimol and CDP was attenuated by pretreatment with flumazenil or bicuculline. From these results, we conclude that GABAergic systems play an important role in the BZP-induced impairment of passive avoidance.

Mediation of dopamine D1 and D2 receptors in the effects of GBR 12909 on latent learning and locomotor activity in mice

We investigated the involvement of dopamine D1 and D2 receptor subtypes in the effects of GBR 12909, a selective dopamine uptake inhibitor, on latent learning in the performance of a water-finding task and on locomotor activity in mice. GBR 12909 (10 and 20 mg/kg) impaired latent learning, and this effect was counteracted by the dopamine D2 receptor antagonist, (-)-sulpiride (20 and 40 mg/kg), but not by the dopamine D1 receptor antagonist, SCH 23390 (0.025 and 0.05 mg/kg). The dopamine D2 receptor agonist, quinpirole (0.5 and 1 mg/kg) and the dopamine D1 receptor agonist, SKF 38393 (20 mg/kg) impaired latent learning, but both effects were less than that of GBR-12909. The effect of quinpirole, but not of GBR 12909, on latent learning was potentiated by combination with SKF 38393. In contrast to its effect on learning, SCH 23390 (0.025 and 0.05 mg/kg) was more effective to suppress the stimulant effect of GBR 12909 on locomotor activity than was (-)-sulpiride (40 and 80 mg/kg). These findings suggest that both dopamine D1 and D2 receptors play an important role in the action of endogenously released dopamine in latent learning and locomotor activity, and that while the dopamine D2 receptor is involved predominantly in latent learning, both dopamine D1 and D2 receptors play a critical role in locomotor activity.

Calcium entry blocking activities of MPC-1304 and of its enantiomers and metabolites

The Ca2+ entry blocking effects of MPC-1304, a new Ca2+ entry blocker of the 1,4-dihydropyridine type, and of its (S) and (R) enantiomers and metabolites were examined on Ca(2+)-induced contractions in isolated rabbit arteries. The Ca2+ entry blocking activity of the (S) enantiomer of MPC-1304 was approximately 150 times greater than that of its (R) enantiomer. Likewise, the antihypertensive effect of the (S) enantiomer was twice as great as that of MPC-1304 (racemate) in conscious spontaneously hypertensive rats, while the (R) enantiomer was ineffective. Thus, most of the pharmacological activity of MPC-1304 resides in its (S) configuration. The main metabolic products of MPC-1304 also inhibited the Ca(2+)-induced contraction in the isolated vascular smooth muscles. These active metabolites showed a stereoselectivity similar to that of MPC-1304 for Ca2+ entry blocking activity, and may contribute to the potent antihypertensive action of MPC-1304.

Cardiovascular profile of MPC-1304, a novel dihydropyridine calcium antagonist : comparison with other calcium antagonists

The cardiovascular profile of a novel calcium antagonist, MPC-1304 and its active metabolites were investigated in experimental animals in vitro and in vivo, and were compared with those of other calcium antagonists or nitroglycerin (NTG). The ratio of negative chronotropic/negative inotropic effect of MPC-1304 was 23 times higher than that of nifedipine in paced left and spontaneously beating right atria of guinea pigs. MPC-1304 and nifedipine did not change atrial-His (AH) conduction time or His-ventricular (HV) conduction time at hypotensive doses in open-chest dogs, whereas diltiazem prolonged AH time. MPC-1304 increased coronary blood flow, and strongly decreased myocardial oxygen consumption (MVO2) by decreasing blood pressure (BP) and heart rate (HR) in open-chest dogs. Left ventricular pressure (LVP) was not changed. Contractile force (dp/dt) was slightly increased by its action on afterload. MPC-1304 and nifedipine did not dilate the large coronary artery, but NTG did. MPC-1304 increased blood flow of the peripheral arteries, especially vertebral and CBF in anesthetized dogs. Cerebral blood flow (CBF) also increased. MPC-1304 decreased serum cholesterol levels and the plaque area of the aorta in cholesterol-fed rabbits. Because of this cardiovascular profile, MPC-1304 should be useful in treatment of hypertension as well as angina pectoris.

Effects of imidazoline-related compounds on the mechanical response to nicorandil in the rat portal vein

The purpose of this study was to investigate the interactions of compounds structurally related to imidazoline at K+ channels located in the rat portal vein. Nicorandil, a K+ channel activator, dose dependently inhibited spontaneous contractions of the isolated rat portal vein. Glibenclamide (0.1-1 microM), an ATP-sensitive K+ channel blocker, competitively antagonized the response to nicorandil, whereas methylene blue (10 microM), a guanylate cyclase inhibitor, did not. Phentolamine, antazoline, tolazoline, and midaglizole also shifted the dose-response curve for nicorandil to the right in the dose range of 1-100 microM. The rank order of potency was glibenclamide much greater than phentolamine = antazoline = midaglizole greater than tolazoline. In contrast, clonidine, idazoxan, imidazole, 1-benzylimidazole, and yohimbine were ineffective. In addition, cromakalim (1-100 nM), a selective K+ channel activator, also inhibited spontaneous contractions of the rat portal vein, and this effect was antagonized by phentolamine in a similar way to that found with nicorandil. These results suggest that some 2-substituted imidazolines, including phentolamine, possibly act as K+ channel blockers, like glibenclamide, in vascular smooth muscle.