Biomedical subjects
Publications and source records attributed to Y Mizuki.
Conjugate pendular nystagmus evoked by accommodative vergence in a healthy 18-year-old girl is described. This is clinically demonstrated to be induced by accommodative convergence, and not related to fusional convergence. The lack of neurological or ophthalmic abnormalities supports the classification of a 'congenital' type of this rare phenomenon. A differential diagnosis is also discussed.
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The averaged photopalpebral reflex (PPR) is an index which objectively assesses the arousal level of humans. The dose-response curve of flunitrazepam, a benzodiazepine derivative, was investigated by using PPR in the present study. Ten healthy male university students were given flunitrazepam 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and placebo in a double-blind, crossover design. PPR and subjective assessment were recorded before and after drug administration. P1 and P2 latencies of PPR were prolonged by flunitrazepam 0.5 mg, 1.0 mg and 1.5 mg in a dose-dependent manner. The prolongation of latencies by flunitrazepam 2.0 mg was weaker than that by 1.5 mg, but was more potent than that by 1.0 mg. In self-assessments, sleepiness, muscle weakness and vagueness of thought were observed after drug ingestion. Sleepiness was correlated with the prolongation of the PPR latencies. These results suggest that PPR could be a useful tool for psychopharmacological investigations in normal humans, that flunitrazepam might be a clinically potent hypnotic drug, and that its peak effect occurs 2-3 h after administration.
When rats were exposed to immobilization stress for 1-12 h, gastric lesions did not occur at 1-6 h but did at 12 h of immobilization. Exogenous adenosine increased stress-induced gastric lesions, and dipyridamole, a blocker of adenosine uptake, potentiated the action of adenosine. The selective adenosine A1-receptor stimulants N6-cyclohexyl adenosine (CHA) and N6-(L-phenylisopropyl) adenosine (L-PIA) produced gastric lesions even in non-stressed state and markedly potentiated in dose- and time-dependent manner in stressed state. The stimulatory effect of N6-(D-phenylisopropyl) adenosine (D-PIA) on ulceration was weaker than that of CHA or L-PIA. Furthermore, intracerebral ventricular (i.c.v.) injection of adenosine or adenosine analogues produced the most rapid and most potent exacerbation of stress-induced gastric lesions relative to those induced with subcutaneous (s.c.) injection. The stress lesions enhanced by CHA were not affected by phentolamine, yohimbine, prazosin, naloxone and cholecystokinin (CCK8) but were inhibited by caffeine, clonidine, morphine and beta-endorphin. The inhibitory effect of clonidine was not antagonized by yohimbine or prazosin. The inhibition by morphine was selectively antagonized by exogenous CCK8 as well as naloxone. These results suggest that endogenous adenosine is tonically active in stress lesion formation which is modulated by opiate systems. Clonidine as well as caffeine may function as a purinoceptor antagonist, and it seems unlikely that the inhibitory effect of clonidine on stress ulcer is due to activation of alpha-adrenoceptors.
Previously we have found that lithium chloride (250 mg/kg i.p.) plus haloperidol (4 mg/kg i.p.), or apomorphine (0.25 mg/kg i.p.) plus thyrotropin releasing hormone (TRH, 20 mg/kg i.p.), elicited a jumping behavior which involves dopaminergic and cholinergic inhibition, and noradrenergic activation. Pretreatment with antiserotonergic agents such as methysergide (5 and 10 mg/kg i.p.) and cyproheptadine (5 mg/kg i.p.) enhanced the jumping behavior induced by these drugs. 5-Methoxy-N,N-dimethyltryptamine (5-MDMT, 5 mg/kg i.p.), a serotonergic receptor agonist, inhibited the jumping behavior. Muscimol, a GABA receptor agonist, at 2 mg/kg, potentiated jumping. GABA receptor antagonists such as bicuculline (4 mg/kg i.p.) and picrotoxin (0.2 and 1 mg/kg i.p.) depressed jumping. An antihistamine agent, diphenhydramine (5 mg/kg i.p.), also potentiated the jumping behavior. Furthermore methysergide (10 mg/kg i.p.), but not muscimol (2 mg/kg i.p.) elicited jumping behavior when combined with clonidine (0.5 mg/kg i.p.), TRH (20 mg/kg i.p.), haloperidol (4 mg/kg i.p.) or atropine (5 mg/kg i.p.). These results suggest that in addition to dopaminergic, cholinergic and noradrenergic mechanisms, serotonergic inhibition may be directly contributing to the initiation of jumping behavior, whereas GABAergic activation appears to be a modulating factor in this behavior.
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The effects of a new benzodiazepine derivative, ethyl loflazepate (CM6912), on the arousal level of normal male human subjects were investigated by use of the averaged photopalpebral reflex (PPR), the latency of which is sensitively prolonged with the lowering of the arousal level. Four doses of ethyl loflazepate, i.e., 2 mg, 4 mg, 6 mg, and 8 mg, and a placebo were administered to each subject 30 min after lunch according to a double-blind, crossover design. Ethyl loflazepate prolonged both latencies of PPR in a dose-dependent manner. The dose-response curves for both latencies, derived from the maximum prolongation, showed a definite and linear dose-response relationship. The drug action occurred within 1 h, peaked at 2.5-3 h, and continued slightly even 4 h after medication. In the subjective assessments, vagueness of thought, sleepiness, and weakness were only slightly observed. These results suggest that ethyl loflazepate could be a potent hypnotic and/or anxiolytic which possesses a relatively rapid onset of action with moderate duration and has no severe side effects.
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Apomorphine, a dopamine receptor agonist, physostigmine, an anticholinesterase agent and pilocarpine, a cholinergic receptor agonist, produced yawning in rats, with the most effective doses being 0.25 mg/kg, 0.2 mg/kg and 4 mg/kg, respectively. The yawning induced by these drugs is characterized by differences in direction of head moving, tongue protruding and duration of the yawn. The apomorphine-induced yawn was characterized by a slow and wide opening of the mouth with the head moving mainly downward and with a marked protrusion of the tongue. The apomorphine-induced yawn was 3.6 sec in duration. Physostigmine elicited a similar yawn to that seen with apomorphine, except for moving of the head in the upward direction. The pilocarpine-induced yawn was characterized by the head moving forward with a high frequency but without tongue protrusion and lasted 1.8 sec. The frequency of physiological yawning was low, but the behavioral posture was almost similar to that of physostigmine-induced yawning. The characteristics of yawns induced by these agents were unchanged at all doses of the drugs. Different doses altered the frequency of yawning. After pretreatment with mecamylamine, the apomorphine- and physostigmine-induced tongue protruding was inhibited and the duration of the yawning induced by the both drugs was shortened. The results suggest that the behavioral features of yawning induced by apomorphine, physostigmine and pilocarpine differ from one another, and that physiological yawning as well as physostigmine-induced yawning may be mediated by endogenous acetylcholine which stimulates both muscarinic and nicotinic receptors.
The distinct theta rhythm in the frontal midline area during a performance of mental tasks has been called Fm theta. However, Fm theta shows individual differences in its appearance. The relationship between the appearance of Fm theta and the subject personality was investigated in the present study. Forty male university students performed an arithmetic addition test for 5 min daily during three consecutive days and their EEGs were recorded during the test. They also completed the Maudsley Personality Inventory (MPI) and the Taylor Manifest Anxiety Scale (MAS) after the EEG recording on the last day. The subjects who obtained low scores on the anxiety scale of MAS, high scores on the extraversion scale of MPI and low scores on the neuroticism scale of MPI showed larger amounts of Fm theta. On the other hand, those subjects who showed high scores on the anxiety scale, low scores on the extraversion scale and high scores on the neuroticism scale showed smaller amounts of Fm theta or none. These results suggest that the appearance of Fm theta is closely related to the subject personality traits.
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Chronic treatment with haloperidol, physostigmine and scopolamine exerted different effects on the frequency of yawning induced by apomorphine (0.25 mg/kg, i.p.), physostigmine (0.2 mg/kg, i.p.) and pilocarpine (4 mg/kg, i.p.) as compared with chronic treatment with saline. Haloperidol decreased the apomorphine- and physostigmine-induced yawning but not the pilocarpine-induced yawning. Physostigmine reduced only the pilocarpine-induced yawning without affecting the apomorphine- and physostigmine-induced yawning. However, physostigmine showed the most rapid onset- and peak-time of yawning induced by a high dose of physostigmine (0.75 mg/kg, i.p.) as well as that of pilocarpine (8 mg/kg, i.p.), and potentiated apomorphine (1 mg/kg, i.p.)-induced stereotypy, as compared with that observed in the saline group. Scopolamine potentiated the physostigmine- and pilocarpine-induced yawning but not the apomorphine-induced yawning. A single pretreatment with scopolamine (0.5 mg/kg, i.p.), however, depressed these yawning responses. The results suggest that yawning induced by physostigmine, but not by pilocarpine, may be modified by long-term treatment with haloperidol. The stereotypy mediated by the postsynaptic dopaminergic system, but not the yawning mediated by the presynaptic system, may be altered by chronic treatment with physostigmine, while long-term treatment with scopolamine seems to produce a supersensitivity to cholinergic receptors.
The theta activity which appears in the frontal midline area during performance of mental tasks has been designated as "Fm theta". In the present study, the possible use of zopiclone as an anxiolytic agent was investigated using Fm theta, in a comparison with diazepam. Sixteen male university students were given placebo, diazepam 5 mg, zopiclone 5 mg and 10 mg, in a double-blind, cross-over design. EEGs were recorded before and during performance of an arithmetic addition test. This test was repeated twice, prior to and 1 h following drug administration. Diazepam markedly increased Fm theta; however, both zopiclone 10 mg and placebo only slightly affected Fm theta, while zopiclone 5 mg failed to affect Fm theta. Scores of state anxiety were reduced markedly by diazepam and only slightly by zopiclone 10 mg, but were not affected by either zopiclone 5 mg or by placebo. Task performance was reduced markedly and in a dose-dependent manner by zopiclone, and very slightly by diazepam. These results suggest that zopiclone possesses a rather potent hypnotic effect, rather than an anxiolytic effect, and that Fm theta might be a useful tool in predicting the clinical efficacy of anxiolytic drugs in normal humans.
The averaged photopalpebral reflex (PPR) represents the mean of summed reflex contractions of the orbicularis oculi muscle in response to periodic photic stimuli. The latency of PPR can be used to assess a drug effect on human arousal level, since it is prolonged if there is a reduction in the arousal level of the subject. In the present study of the clinical effects of zopiclone, healthy male volunteers aged 18-22 years were given zopiclone 5 mg and 10 mg, nitrazepam 5 mg and 10 mg, or placebo, in a double-blind, cross-over design. Changes in the latencies of PPR were examined from 0.5 to 4 h after medication. Both zopiclone and nitrazepam prolonged the latency in a dose-dependent manner, but the prolongation induced by zopiclone appeared more rapidly, was slightly more marked and lasted for a shorter period than that induced by nitrazepam. Zopiclone produced slightly fewer subjective changes, such as vagueness of thought and weakness, than did nitrazepam. From these results, it is suggested that zopiclone possesses a potent hypnotic action which appears more rapidly and is slightly more potent and shorter lasting than that of nitrazepam. In addition, zopiclone may also exhibit fewer side effects, such as vagueness of thought and weakness than nitrazepam, and it may cause less "hang over".
The photopalpebral reflex (PPR) is a useful method to assess level of arousal. Healthy males were given either brotizolam (0.0625, 0.125, 0.25 or 0.5 mg) or placebo within a double-blind, crossover design. Changes in PPR and subjective assessments were observed for 5 h after medication. Prolongation of the latencies of PPR were dose dependent, and the amplitude tended to be reduced. These effects appeared within 30 min, and lasted about 4 h. The dose-response curve of the maximum prolongation of the latencies was linear. Sleepiness and slight ataxia were observed after drug ingestion. Sleepiness was correlated with the prolongation of the PPR latencies. Brotizolam could be a potent hypnotic, with rapid onset and moderate duration of action, and it has no severe side-effects.
The averaged photopalpebral reflex (PPR) was bipolarly recorded from electrodes placed on the upper and lower palpebrae in male university students. In a drowsy state which was defined by the monitored EEG, the latencies of PPR were significantly prolonged and the amplitude reduced. In contrast, the latencies were shortened by immersing their hands in ice water which greatly aroused the subjects. The central stimulant, methylphenidate 10 mg, significantly shortened the latencies and diazepam 5 mg possessing anxiolytic and hypnotic actions significantly prolonged them. When the recording of PPR was repeated consecutively five times, the amplitude was easily reduced but the latencies were relatively stable. From these results, it is confirmed that the latencies of PPR are prolonged in a lowered arousal level and shortened in a more aroused state. This indicates that PPR could be a useful index to assess objectively the arousal level of humans and hence could be a useful tool for investigations of psychophysiology and psychopharmacology.
The clinical effects of zopiclone were predicted by using two psychophysiological tests: the averaged photopalpebral reflex and the frontal midline theta activity. Zopiclone at 5 and 10 mg showed a rapid, dose-dependent, moderately lasting prolongation of the latencies of the averaged photopalpebral reflex related to the lowering of the arousal level. Diazepam 5 mg increased markedly the frontal midline theta activity, the appearance of which seems to be related to the relief from anxiety, while zopiclone 10 mg only slightly modified the frontal midline theta activity. The results suggest that zopiclone possesses a potent hypnotic effect, whereas its anxiolytic potential in humans is probably low.
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