Masahiro Nomoto

Ketamine-induced anesthesia involves the N-methyl-d-aspartate receptor-channel complex in mice

The role of the N-methyl-D-aspartate (NMDA) receptor-channel complex in ketamine-induced anesthesia was examined in mice. General anesthetic potencies were evaluated on a rating scale, which provided the data for anesthetic scores, loss of righting reflex, sleeping time and recovery time. All drugs were administered intraperitoneally. NMDA (60-300 mg/kg), an NMDA receptor agonist, dose-dependently antagonized the general anesthetic potencies of ketamine at a dose of 100 mg/kg which produced loss of righting reflex in more than 90% of the mice. On the other hand, a high dose of N-methyl-L-aspartate (400 mg/kg), a stereoisomer of NMDA, did not. A dose of 300 mg/kg of NMDA significantly shifted the dose-response curve of ketamine for loss of righting reflex to the right. A high dose of D-cycloserine (200 mg/kg), an agonist at the glycine site on the NMDA receptor complex, slightly but significantly shortened the sleeping time caused by ketamine (100 mg/kg). However, neither a critical subconvulsive dose of kainate (15 mg/kg), a kainate receptor agonist, nor a subconvulsive dose of quisqualate (120 mg/kg), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonist, reversed general anesthesia induced by 100 mg/kg of ketamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice.

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)

Chronic estrogen treatment replaces striatal dopaminergic function in ovariectomized rats

Eight-week-old female Sprague-Dawley rats were divided into three groups: ovariectomized rats (OVX); ovariectomized rats treated with estradiol valerate (E2), 20 microg subcutaneously (s.c.) twice weekly for 12 weeks (OVX+E2 group); and sham-operated control rats treated with vehicle alone (controls). Spontaneous locomotor activity was measured for 24 h, and then again after the administration of methamphetamine (1 mg/kg, i.p.). In addition, striatal contents of dopamine (DA) and its metabolites were measured. Using an in vivo microdialysis technique, changes in extracellular striatal dopamine concentration were studied in a separate set of similarly treated rats after the administration of methamphetamine (0.2 mg/kg, i.p.). Spontaneous locomotor activity decreased in the OVX group, and estradiol replacement reversed this decreased activity. No significant differences were observed in the contents of DA and its metabolites at the striatum among the three groups. The basal output of DA at the striatum was lower in the OVX group than in those of the other two groups. Extracellular DA concentration following methamphetamine administration was also lower in the rats of OVX group. These results indicate that ovariectomy decreases spontaneous locomotor activity, response to methamphetamine, and striatal DA release in the female rats. Chronic replacement of estrogen reversed spontaneous locomotor activity and DA release by the striatum. These results suggest that chronic administration of estrogen may be beneficial in the treatment of female menopausal patients with Parkinsons disease.

Involvement of N-methyl-D-aspartate (NMDA) receptors in noncompetitive NMDA receptor antagonist-induced hyperlocomotion in mice

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.

Neopterin in cerebrospinal fluid : a useful marker for diagnosis of HTLV-I-associated myelopathy/tropical spastic paraparesis

Neopterin is a pyrazino-pyrimidine compound that is biosynthesized from guanosine triphosphate.’ Neopterin may be an in vitro indicator of activation of the immune system. Raised excretion of neopterin is related to the action of interferons on the T lymphocyte/macrophage axis.* Increased urinary neopterin levels occur in patients with malignancies and viral infections, as well as in patients with the acquired immunodeficiency syndrome (AIDS) and generalized lymphadenopathy.3-5 We have measured the levels of neopterin in human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HAM/TSP is a chronic progressive myelopathy characterized clinically by a symmetric upper motoneuron disorder with urinary sphincter involvement and mild sensory disturbances, and serologically by the presence of antibodies against HTLV-I in serum and CSF.6 Methods. Twenty patients with HAM/TSP, 17 asymptomatic HTLV-I carriers, 6 patients with viral encephalitis, 30 patients with other neurologic disorders, including 6 cases of chronic MS, and 26 normal controls were analyzed. The assay for neopterin involved a pretreatment modified from that of Fukushima and N i ~ o n . ~ CSF and urinary neopterin levels were measured by high-pressure liquid chromatography (HPLC) with fluorometric detection. Each CSF sample (100 pl) was thawed and immediately acidified with 100 pl of ice-cold 0.1 N HCI and kept in ice. Then, 50 1 1 of a 1% 12/2% KI in 0.1 N HCl was added and allowed to react a t room temperature in the dark. After standing for 60 minutes, the mixture was neutralized with 50 1 1 of 1.5% ascorbic acid. The solution was centrifuged at high speed for 1 minute in a Beckmann microcentrifuge. For HPLC, a 100-p1 sample of the supernatant was injected over a C18 column (250 X 4.6 mm) with 7% methanol in water as the mobile phase. The neopterin assay was standardized with similarly treated authentic standards. Results. CSF neopterin values in controls (18.0 ? 5.3 pmol/ml, mean k SD) were in agreement with others. Extremely high values of CSF neopterin were found in patients with HAM/TSP (107.7 f 98.1; p < 0.001, Fisher’s exact test). Patients with viral encephalitides also showed high levels of neopterin in CSF. Other noninflammatory neurologic disorders such as MS, ALS, Parkinson’s disease, or cervical spondylosis showed CSF neopterin levels similar to those of the controls, with values below 30 pmol/ml (figure). Some cases of HAM show mild CSFpleocytosis. However, there was no significant correlation between cell counts and levels of neopterin in CSF. Urine samples were measured after being diluted 100 times. Urinary neopterin levels

Effects of ketamine on dopamine metabolism during anesthesia in discrete brain regions in mice: comparison with the effects during the recovery and subanesthetic phases

The effects of ketamine on the levels of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT, serotonin) and their metabolites were examined in discrete brain regions in mice. A high dose of ketamine (150 mg/kg, i.p.) did not change DA metabolism in the frontal cortex, nucleus accumbens, striatum and hippocampus, but did decrease it in the brainstem during anesthesia. In contrast, during recovery from the ketamine anesthesia, the high dose increased the level of homovanillic acid (HVA) in all brain regions. A low subanesthetic dose of ketamine (30 mg/kg, i.p.) increased the concentrations of both 3,4-dihydroxyphenylacetic acid (DOPAC) and HVA only in the nucleus accumbens. The DA level was not affected by any ketamine treatment. During ketamine anesthesia, the content of 3-methoxy-4-hydroxy-phenylglycol (MHPG) was decreased in the brainstem, whereas during recovery from anesthesia, the MHPG level was increased in the frontal cortex, nucleus accumbens and brainstem. The NE content was not altered in any region by ketamine treatment. The concentration of 5-hydroxyindoleacetic acid (5-HIAA) was reduced in the frontal cortex, striatum, hippocampus and brainstem during ketamine anesthesia. The 5-HT level was unaltered in all regions except the brainstem where it was reduced. In contrast, after anesthesia, the concentrations of both 5-HT and 5-HIAA were increased in the striatum. During the subanesthetic phase, however, the levels of NE, 5-HT and their metabolites were unchanged. These neurochemical results are consistent with the electrophysiological findings that a high dose of ketamine does not change the basal firing rates of nigrostriatal DA neurons during anesthesia, while low subanesthetic doses significantly increase those of ventral tegmental DA neurons.

Effect of selegiline on dopamine concentration in the striatum of a primate

Monoamine oxidase (MAO) has two subtypes, A and B, that have different distributions between the rodent and the human. In the striatum, dopamine (DA) of the rat seems to be metabolized by MAO A, and DA of the human is largely deaminated by MAO B. MAO in the striatum of common marmosets is also type B. Using in vivo microdialysis, we investigated the pharmacological activity of selegiline, a selective irreversible inhibitor of MAO B, in the striatum of marmosets. Intraperitoneal co-administration of selegiline (1 mg kg-1, i.p.) with levodopa/carbidopa (10/2.5 mg kg-1, i.p.) did not significantly increase extracellular concentration of DA in the striatum of common marmosets compared with control animals receiving levodopa/carbidopa alone. Daily pretreatment with 0.1 mg kg-1 (i.p.) selegiline for two weeks, however, dramatically increased extracellular concentration of DA to about seven times that of control animals treated with levodopa/carbidopa alone in marmosets. Such an increase in extracellular concentrations of DA could not be observed in a similar study with Wistar rats. This study showed that chronic administration of a small dose of selegiline caused a marked increase in extracellular DA concentration in the striatum of primates, but not in the rodents.

The metabolic rate and vulnerability of dopaminergic neurons, and adenosine dynamics in the cerebral cortex, nucleus accumbens, caudate nucleus, and putamen of the common marmoset.

Abstract The pathophysiology of the striatum and cerebral cortex were studied from the pharmacological aspect.Investigation of the dopamine content in the cerebral cortex revealed that the premotor and motor area showed the highest level (61±6.2 ng/g). Intravenous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose of 10 mg/kg reduced the dopamine content in the caudate nucleus and putamen to 2–3% of the control level in common marmosets, while it fell to 60% in the nucleus accumbens. There was no alteration of the dopamine content in the cerebral cortex. Immunohistochemical staining for tyrosine hydroxylase in the midbrains of MPTP-treated marmosets showed almost complete disappearance of dopaminergic cells from the substantia nigra and good preservation of cells in the ventrotegmental area. Dopaminergic cells projecting to the caudate/putamen, nucleus accumbens, and cerebral cortex showed marked, moderate, and no vulnerability to MPTP, respectively.After systemic administration of MPTP, dopaminergic neurons projecting to the caudate nucleus and putamen were damaged equally. However, the compensatory increase of dopamine turnover was more prominent in the putamen than in the caudate nucleus. Thus, nigroputaminal dopaminergic neurons may have a higher level of activity than neuron in the caudate. The neural connections and functions of the caudate nucleus and putamen have already been differentiated anatomically or physiologically. This compensatory increase of the dopamine turnover rate is another aspect of functional differences between the caudate nucleus and putamen.Investigation of the dopamine content in the heat, body, and tail of the caudate nucleus showed no differences in the concentration of dopamine. However, a study of the metabolic rate of dopamine using α-methyl-p-tyrosine, a tyrosine hydoxylase inhibitor, showed higher metabolism of dopamine in the head of the caudate nucleus in common marmosets. Thus, dopaminergic neurons projecting to the caudate nucleus may show topographical differences in their firing rates.A microdialysis study indicated an increase in the metabolism of adenosine in the striatum of MPTP-treated animals. Cholinergic neurons are interneurons and are one of the main sources of adenosine in the striatum. Dopaminergic input from the substantia nigra acting on cholinergic neurons was decreased following MPTP treatment. The increase of adenosine metabolism suggested that cholinergic neurons in the striatum receive inhibitory inputs from nigrostriatal dopaminergic neurons.

Postural myoclonus associated with long-term administration of neuroleptics in schizophrenic patients

Postural myoclonus associated with long-term administration of neuroleptics was demonstrated in schizophrenic patients. Sixty patients who had been taking neuroleptics for more than 3 months were investigated for myoclonus and the relationships between postural myoclonus and age, duration of illness, duration of medication, current daily dose, cumulative dose, occurrence of abnormal finger movement, parkinsonism, and tardive dyskinesia were evaluated. Twenty-three patients (38%) showed postural myoclonus when holding the hands forward with the elbow joints flexed at about 90%. Male patients showed a higher incidence of myoclonus than female patients. Patients with myoclonus had been given significantly higher doses of neuroleptics than those without myoclonus. There was a significant correlation between the occurrence of myoclonus and abnormal finger movement. Electromyographic recordings in 7 patients with prominent myoclonus revealed that arrhythmic jerks occurred in the extensor carpi radialis and posterior deltoid muscles and that the jerks on the left and right side were not synchronized. Clonazepam reduced the frequency of the myoclonic activity.

Effects of Acute or Prolonged Administration of Cabergoline on Parkinsonism Induced by MPTP in Common Marmosets

The effects of a single treatment or chronic administration of cabergoline (1-[(6-allylergolin-8beta-yl)carbonyl]-1-[3-(dimethylamino)p ropyl]-3-ethyl-urea), a potent, long-lasting dopamine receptor agonist, on parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in common marmosets were studied. The administration of 0.2 mg/kg or a higer dose of cabergoline began to reverse parkinsonism-like symptoms 60 min after a subcutaneous injection, and showed steady and constant effects throughout the observation period. For prolonged administration, 0.2 mg/kg cabergoline was injected daily for 22 consecutive days. Locomotor activity in MPTP-treated animals increased until it reached its peak on the third day, then it gradually decreased. Akinesia scores, rating the quality of movements, were also improved, and the improvement was sustained up to the last day of chronic administration. None of the animals developed abnormal behaviors after either acute or chronic administration. These results suggest that cabergoline has long-acting effects in the marmoset model of parkinsonism, and that it will be a useful agent for the treatment of Parkinsons disease, particularly in cases with fluctuating motor disabilities.