Takeshi Koja

Corneal lesions induced by the systemic administration of capsaicin in neonatal mice and rats

SummaryFollowing a single subeutaneous injection of capsaicin to neonatal mice, a high incidence of corneal lesions with opacity developed after a long latency. The intensity of the lesions progressed for about 1 month in animals which had received a high dose (50 or 100 mg/kg) of capsaicin. Although the intensity gradually decreased thereafter, 50% of animals still exhibited a visible opacity 6 months after treatment. Similar corneal lesions were also produced in neonatal rats which had been injected with capsaicin. It is suggested that the corneal lesions induced by capsaicin may be due to destruction of the trigeminal nerve.

Effects of methysergide and naloxone on analgesia induced by the peripheral electric stimulation in mice

We investigated the antinociceptive effects produced by peripheral electric stimulation (PES) in mice and the influence of administration of L-5-hydroxytryptophan (5-HTP), methysergide and naloxone on the antinociceptive effect of the PES. Administration of 5-HTP enhanced antinociceptive effects induced by PES, while methysergide and naloxone abolished this antinociception. The mechanisms of analgesia produced by PES involve both endogenous opiate systems and central serotonergic mechanisms.

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.

Anti-tremor activity of talipexole produced by selective dopamine D2 receptor stimulation in cynomolgus monkeys with unilateral lesions in the ventromedial tegmentum

The anti-tremor activity of talipexole (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine dihydrochloride, B-HT 920 CL2, Domin), a non-ergot dopamine D2 receptor agonist which possesses alpha 2-adrenoceptor agonistic and 5-HT3 receptor antagonistic properties, was examined in monkeys with a unilateral lesion in the ventromedial tegmentum. Talipexole dose dependently suppressed the tremor and had ED50 values of 34 micrograms/kg s.c. and 84 micrograms/kg p.o. The anti-tremor effect of talipexole occurred at much lower doses than that of an ergot dopamine receptor agonist, bromocriptine (2-bromo-alpha-ergocryptine mesilate, ED50; 2.5 mg/kg s.c.), and talipexole acted synergistically in combination with L-DOPA (3,4-dihydroxyphenylalanine). In ventromedial tegmentum-lesioned monkeys, anti-tremor doses of talipexole did not cause emetic behavior, but had sedative effects. Conversely, monkeys given bromocriptine exhibited oral movement, salivation and vomiting when anti-tremor effects were observed, but not marked sedative behavior at any of the doses investigated. During repeated administration of talipexole (a daily dose of 50 micrograms/kg s.c. for 21 days), the extent and duration of the anti-tremor effect did not change, but those of the sedative effect decreased gradually. The anti-tremor effect of talipexole was significantly suppressed by sulpiride, but not by SCH 23390 (7-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) or yohimbine, while the sedative effect was inhibited by sulpiride and yohimbine. The main metabolites of talipexole had no anti-tremor or sedative effects. These results indicate that talipexole exerts its anti-tremor activity via selective dopamine D2 receptor stimulation.

Effects of new neuroleptics, isofloxythepin and zotepine, on post-decapitation convulsions and prolactin secretion in rats

Oral administration of isofloxythepin (0.5-8.0 mg/kg) inhibited decapitation convulsions in a dose-dependent manner as shown by decreasing the incidence and shortening the convulsions duration, the effects continuing until 24 hr after administration. Zotepine (8, 16 mg/kg, SC) also decreased the duration but not the incidence of the convulsion. However, the other neuroleptics such as haloperidol, spiperone, perphenazine, trifluoperazine, pimozide and sulpiride failed to affect decapitation convulsions. Reserpine (8 mg/kg, SC) inhibited decapitation convulsions, accompanied by decreasing levels of norepinephrine, dopamine and serotonin in the spinal cord. Isofloxythepin at doses of 4 and 8 mg/kg, PO which completely abolished decapitation convulsions, failed to change norepinephrine and dopamine levels but increased serotonin levels in the spinal cord. Isofloxythepin (0.5-8.0 mg/kg) increased serum prolactin levels in a dose-dependent manner and zotepine (16 mg/kg), haloperidol (1 mg/kg) and reserpine (8 mg/kg) also elevated the levels. The results imply that both isofloxythepin and zotepine, but not the other neuroleptics, inhibit convulsions without decreasing spinal levels of norepinephrine which appears to be the amine most directly involved in the occurrence of decapitation convulsions, although these neuroleptics enhance prolactin secretion by blocking dopamine receptors in the pituitary.

Inhibitory effect of taurine on wet-dog shakes produced by [d-Ala2,MET5] enkephalinamide with reference to effects on hippocampal epileptic discharges

The effects of taurine on wet-dog shakes produced by [D-Ala2,Met5]enkephalinamide (DAME) were investigated in rats. Wet-dog shakes and epileptic discharges in the hippocampus were produced by intraventricular administration of 50 micrograms of DAME. Pretreatment with 10 microliter of taurine, given intraventricularly in a dose of 0.95 mumol, inhibited wet-dog shakes and epileptic discharges in the hippocampus. While the same dose of gamma-aminobutyric acid (GABA) also inhibited the wet-dog shakes, the same dose of L-leucine did not suppress them. These observations indicate that the inhibition of DAME-induced wet-dog shakes by taurine is associated with the suppression of seizure activities in the hippocampus. The possibility that taurine possesses an antagonistic action on opioid peptides is discussed.

Meclofenoxate therapy in tardive dyskinesia: A preliminary report

Tardive dyskinesia seems to occur as a result of diminished cholinergic and enhanced dopaminergic activity in the striatum. Meclofenoxate has been shown to increase cerebral cholinergic activity. To ameliorate the tardive dyskinesia, meclofenoxate was given orally, 600-1200 mg/day, for 6-12 weeks. The effects of the drug were evaluated by scoring the degree of involuntary movement. Among 11 subjects with tardive dyskinesia or dystonia, 4 improved markedly, 1 moderately, 2 slightly, and there was no improvement in 4. One patient with subacute oral dyskinesia, induced by administration of neuroleptics for 1 month, improved markedly. The possibility that meclofenoxate may be effective in dealing with dyskinesias that are induced by neuroleptics warrants further attention.

Phenytoin potentiates methamphetamine-induced behavior in mice

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.

Modification of the antiepileptic actions of phenobarbital and phenytoin by the taurine transport inhibitor, guanidinoethane sulfonate

We investigated whether chronic administration of guanidinoethane sulfonate, an inhibitor of taurine uptake, could modify the antiepileptic actions of phenobarbital and phenytoin on maximal electroshock seizures in mice. Treatment with 1% guanidinoethane sulfonate decreased the taurine concentration in the brain to 76% of the control value. Under these conditions, neither the severity of tonic convulsions of maximal electroshock seizures nor the threshold for tonic extension caused by electroshock was altered. However, treatment with guanidinoethane sulfonate lessened the antiepileptic actions of phenobarbital and phenytoin on electroshock seizures. The brain concentrations of phenobarbital and phenytoin were unaltered by administration of guanidinoethane sulfonate. The brain concentrations of guanidinoethane sulfonate and total guanidino compounds were unchanged by the injection of either phenobarbital or phenytoin. It is suggested that the observed loss of anticonvulsive potency of phenobarbital and phenytoin may have been related to the decrease in taurine concentration produced by guanidinoethane sulfonate.

Taurine inhibits wet-dog shakes and hippocampal seizures induced by opioid peptides in rats.

Wet dog shakes (WDS) are paroxysmal shudders of head, neck and trunk. This behavior has been observed when dipping animals into cold water (41), application of xylene to the fur (39) and tactile stimulation around ears (1). Pharmacological studies revealed that WDS can be produced by administration of thyrotropin-releasing hormone (9,24,29,41,42), 5-Hydroxytryptamine (3,12), or kainic acid (5,25). WDS are also known as a classical sign of morphine abstinence in rats (40,43). In 1976, Bloom et al. first reported that this shaking behavior was elicited by acute administration of β-endorphln into the lateral ventricle in rats. Similar observations were made in rats with enkephalin (15). In addition, it was found that epileptic discharges were provoked by the intraventricular (icv) injection of opioid peptides and WDS always accompanied the onset of seizure discharges (15,16,37). These findings suggest that there may be an association between electrical seizure activities and WDS.