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The role of the N-methyl-D-aspartate (NMDA) receptors in hyperlocomotion induced by (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), a potent and selective noncompetitive NMDA receptor antagonist, was examined in male ddY mice. A low dose of MK-801 [0.2 mg/kg, intraperitoneally (IP)] produced a marked increase in locomotor activity without obvious staggering gait. In contrast, a high dose (1 mg/kg, IP) induced a typical motor syndrome characterized by increased locomotor activity, stereotyped behavior, and severe ataxia. NMDA (60-120 mg/kg, IP), an NMDA receptor agonist, dose dependently antagonized hyperlocomotion induced by a low dose of MK-801 (0.2 mg/kg). However, even a high convulsive dose of NMDA (240 mg/kg, IP) could not completely antagonize the hyperactivity induced by MK-801. On the other hand, neither a high dose of N-methyl-L-aspartate (400 mg/kg, IP), a stereoisomer of NMDA, nor a critical subconvulsive dose of kainate (10 mg/kg, IP), a non-NMDA receptor agonist, reversed MK-801-induced hyperlocomotion. The activity induced by MK-801 was potently suppressed by low doses of haloperidol (0.05-0.1 mg/kg, IP), a dopamine (DA) receptor antagonist, in a dose-dependent manner. These data for MK-801 were similar to those for phencyclidine and ketamine, other noncompetitive NMDA receptor antagonists. These results suggest that noncompetitive NMDA receptor antagonist-induced hyperlocomotion is mediated, at least in part, by NMDA receptor antagonism, although this hyperactivity may also involve dopaminergic mechanisms through indirect (perhaps by reducing NMDA receptor-mediated neurotransmission) and/or direct (by inhibiting DA uptake) effects on DA neurons.

We studied the effect of various kinds of beta-adrenergic blockers on oxotremorine-, harmaline- and thyrotropin-releasing hormone (TRH)-induced tremors in mice. To investigate what property of beta-blockers plays the main role in suppressing tremor, we employed five beta-blockers (propranolol, atenolol, butoxamine, pindolol, and arotinolol). All drugs suppressed oxotremorine-induced tremors but none reduced harmaline-induced tremors. Even though TRH-induced tremors were decreased significantly only by propranolol and high doses of arotinolol, all drugs had a tendency to reduce the tremor. We concluded that neuropharmacological mechanisms underlying to harmaline-induced tremors were different from those of TRH- and oxotremorine-induced tremors and that features of beta-blockers (beta 1- or beta 2-selectivity, intrinsic sympathomimetic activity, and membrane stabilizing activity) did not primarily contribute to the suppression of tremors.

The incidence of haloperidol-induced catalepsy was investigated in mice whose postsynaptic dopamine (DA) receptors in the striatum had been upregulated by denervation with 6-hydroxydopamine (6-OHDA). In nonupregulated mice, which were injected with 6-OHDA 4 days before, DA in the striatum fell to 21% of the level found in vehicle-injected mice but [3H]spiperone binding to the membrane of the striatum did not increase. In upregulated mice, which were injected with 6-OHDA 28 days before, DA was at 24% and [3H]spiperone binding increased by 15%. The ED50 values (with 95% confidence limits) for haloperidol-induced catalepsy in nonupregulated mice and that in upregulated mice was 0.40 mg/kg (0.25-0.65 mg/kg) and 0.29 mg/kg (0.16-0.51 mg/kg), respectively. There was no significant difference in the incidence of catalepsy between the two groups of mice. This suggests that the intensity of catalepsy produced by the DA receptor blockade may be unaltered even when the density of receptors increases.

The underlying mechanisms of ketamine-induced hyperlocomotion were examined in mice. An intraperitoneal (IP) injection of ketamine (3-150 mg/kg) increased locomotor activity in a dose-dependent fashion. A low dose of ketamine (30 mg/kg) produced peak locomotion within the first 10 min followed by a rapid decline. In contrast, a high dose (150 mg/kg) inhibited locomotor activity to the control level during the first 30 min. Thereafter the activity gradually increased and reached a peak at approximately 2 h followed by a gradual decline. The hyperactivities induced by both low and high doses of ketamine were inhibited by a low dose of haloperidol (0.10 mg/kg, IP), a dopamine (DA) receptor antagonist. However, neither a high dose of phenoxybenzamine (10 mg/kg, IP), an alpha-blocker nor a high dose of propranolol (20 mg/kg, IP), a beta-blocker inhibited the hyperactivities. Destruction of catecholaminergic terminals by 6-hydroxydopamine suppressed ketamine-induced hyperlocomotion. Regional brain monoamine assays revealed that, at peak locomotion, a low dose of ketamine (30 mg/kg) selectively increased DA turnover in the nucleus accumbens which is a forebrain region believed to be involved in the initiation and regulation of locomotor activity, while a high dose (150 mg/kg) increased not only DA but also norepinephrine and serotonin turnover in many regions of the brain. In vitro, ketamine slightly provoked [3H]DA release from nucleus accumbens and striatal slices to a similar extent, but inhibited synaptosomal uptake of [3H]DA in the nucleus accumbens to a greater degree than in the striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

We demonstrated that stereotyped behavior and tremor induced by methamphetamine (MA) were potentiated by pretreatment with phenytoin (PNT) in mice. Similar enhancing effects were obtained by pretreatment with carbamazepine. Gas chromatographic study demonstrated that pretreatment with PNT increased MA concentrations in the brain to approximately 2.5 times of control level. The increased MA concentrations were thought to be a major factor for the observed potentiation of MA-induced behavior by PNT. However, all MA-induced behavior were not equally potentiated; tremor was enhanced more than stereotypy. These results suggest that central neuronal mechanisms may also be involved in PNT-potentiated MA-induced behavior in mice.