Biomedical subjects
Publications and source records attributed to J Yanai.
Male dogs were injected i.v. with 1 methyl-4-phenyl-1,2,3,6-tetrahydro- pyridine (MPTP) 2.5 mg/kg twice with an interval of 6 days. Twenty minutes after MPTP injection cyclohexyladenosine (CHA) 1 mg/kg i.v. was injected. Ten minutes after CHA injection the MTPT induced tremor, tachycardia and salviation ceased.
Chronic phenobarbital administration for 20 days to mice resulted in significant increases in the density of peripheral benzodiazepine binding sites in the heart, kidney and cerebellum, but did not affect the density of these sites in the olfactory bulb. No alteration in the affinity (KD) of peripheral benzodiazepine binding sites for their ligand [3H]PK 11195 was observed in any of the organs examined. Phenobarbital treatment did not affect the maximal binding capacity or the affinity of the central benzodiazepine receptors for [3H]flunitrazepam in the cerebral cortex, hippocampus and olfactory bulb. A significant reduction in [3H]muscimol binding in the hippocampus was obtained following chronic phenobarbital treatment. Such an alteration was not detected in the cerebral cortex. The KD values remained unaltered in both tissues. The modulatory effect of phenobarbital on peripheral benzodiazepine binding sites could be related to alterations in the functions of these organs or to the neurochemical effects of the drug.
Mice were prenatally exposed to phenobarbital. As adults, these mice (B animals) were deficient in the hippocampally related eight-arm maze performance, a behavior apparently dependent on the integrity of the septohippocampal cholinergic pathways. Preliminary studies suggest possible parallel alterations in their hippocampal cholinergic innervations. The dopaminergic septal innervations are known to indirectly inhibit the septohippocampal cholinergic innervations. Consequently, the septal dopaminergic innervations of adult B mice were destroyed by 6-hydroxydopamine (6-OHDA). Mice treated with 6-OHDA had an improvement in maze performance which was most marked with increased experience. Concomitant increase in choline acetyltransferase (ChAT) was also demonstrated in these mice (79%, P less than 0.001). Similar increase in ChAT could be demonstrated in control mice after 6-OHDA treatment, but the behavioral changes were small and did not reach statistical significance, possibly due to the ceiling effect of the studied behavior. Thus, the dopaminergic innervations in the septum regulate cholinergic activity and its related behaviors along the septohippocampal pathway, and thereby ameliorate behavioral deficits induced by early phenobarbital administration.
The heterogeneous mouse stocks HS/Ibg and SABRA/HUC and the inbred strains C57BL/6J, CBA/LAC, and BALB/Crgl were employed in an investigation of strain differences in delayed spontaneous alteration (SA) and eight-arm maze performance (EAM). Intact male mice were tested for SA at age 41 days for 2 consecutive days and for EAM at age 50-54 days, under conditions of water deprivation that commenced on day 43. In SA, BALB mice had a lower score than all other strains on day 1 but differed significantly only from SABRA; performance on day 2 was not consistent with that on day 1. In EAM, HS was first, CBA second, C57 third, SABRA fourth, and BALB fifth. HS was superior to the other strains, while BALB fell far below all other strains in both tests. Except for these two strains, the correlation between the two tests across the other strains was low. A study was undertaken to investigate the role of the hippocampus in the deficits in the performance of BALB mice in the two behaviors. Noradrenergic neurons were transplanted to hippocampus or cortex, and cholinergic neurons to their hippocampus. There were no significant differences in performance between the control and transplanted mice. The possibility was discussed that the behavioral differences are the outcome of variability in the neurotransmitters systems of the hippocampus but probably not the noradrenergic system.
The anticonvulsants phenobarbital and diphenylhydantoin administered early in life to mice resulted in significant and long-lasting ultrastructural damage, including abnormalities of mitochondria, myelin sheaths, and lamellar inclusion bodies inside identified cells throughout the cortical layers of the cerebellum in treated vs control mice. The magnitude, distribution and duration of damage was age and treatment specific. No differences were detected in density of parallel fiber processes nor in synapse density within the molecular layer. Neuron profiles containing damaged organelles were not homogeneously distributed but made up only a small fraction of the total cell population examined. In our experiments, there was an overall within-animal correlation explaining 45% of the magnitude of damage in different cerebellar regions, but between synaptically connected cells, specifically mossy fiber axon varicosities and granule cell dendrite profiles, the subset population ratio of damaged-to-total mitochondria was highly significantly correlated (70-90%; P less than 0.001). We hypothesized that some correlated transneuronal degeneration and death in the central nervous system may have a transynaptically regulated component that first appears as correlated damage between synaptically connected cells, perhaps regardless of the degree of toxicity. The orderly cytoarchitecture and cell connections of the cerebellar cortex can be used to study these patterns of degeneration.
Results of this investigation show a differential effect of early barbiturate administration on behaviors of mice of two inbred strains in the open field and in the barrier cage. Pups of the inbred strains DBA/l and C57BL/10 were fostered by HS/Ibg dams and were given a daily injection of 50 mg/kg sodium phenobarbital on postnatal days 2-21 (treated groups); control pups received vehicle injections. At 28 and 30 days the animals were tested in an open field and in a barrier cage. The DBA/l mice responded differently from C57BL/10 to early barbiturate treatment. Treated DBA/l mice showed a marked reduction from control levels in open-field locomotion and grooming but not in defecation. In the barrier test, there were reductions in jumping, peeking and grooming and increase in defecation. The differences between controls and treated in the C57BL/10 strain were small except for barrier jumping and peeking. It is suggested that genotype (strain) - environment (drug) interaction exists for the effect of early phenobarbital administration on behavior: DBA/l was sharply affected by the drug, while the behavior of C57BL/10 was little altered by neonatal phenobarbital administration.
Mice who were exposed to phenobarbital prenatally (B mice) had at adulthood deficits in the hippocampal eight-arm maze, spontaneous alternations, and water maze behaviors. Morphological studies revealed neuronal losses in the hippocampus. The surviving neurons had reductions from control in the number of dendritic branches, area and spine density, but wider fission angle than control. Neurochemical studies on the hippocampus revealed the following alterations: (a) decrease in NE level and the number of the NE cell bodies (b) no change in the serotonergic system (c) an increase in muscarinic receptors Bmax in the hippocampus; (d) no changes in GABA and benzodiazepine receptors. However, neonatal phenobarbital exposure caused an increase in the Bmax of GABA and benzodiazepine receptors. Transplantation of fetal septal cholinergic neurons into the hippocampus of B mice reversed most of the deficits in eight-arm maze behavior, while transplantation of noradrenergic cells did not affect the performance of B mice. In further studies on cholinergic mechanisms, the dopaminergic innervations in the septum (originating from A10), which are known to indirectly inhibit the activity of the septohippocampal cholinergic pathways, were destroyed by 6-OHDA. B mice treated with 6-OHDA had an increase in hippocampal ChAT activity and improved their eight-arm maze performance. Thus, understanding of the mechanism of a particular behavioral deficit enables one to correct it despite the nonspecific action of the neuroteratogen.
Twenty-five shoulders were dissected in cadavers in order to observe the presence of the inferior transverse ligament, the spinoglenoid ligament, and its relationship to the spinoglenoid notch and the suprascapular nerve. The ligament was found to be absent in 50% of females and rudimentary in one female, but absent in only 13% of the male shoulders. The distance between the ligament and the bone, and from the ligament to the nerve was similar in males and females, but the variation was greater in males. These findings may explain the observation that distal suprascapular nerve entrapment occurs mostly in men.
Congenital complete atrioventricular block without any other intracardiac anomaly reverted to sinus rhythm at the age of 7 years. The girl had had heart failure and Adams-Stokes attacks when aged 1 year, requiring pacemaker implantation. Electrocardiography confirmed sinus rhythm for the first time at the age of 7 years. At the same time, a treadmill test yielded a normal tracing without any arrhythmias.
Mice were exposed to phenobarbital prenatally on gestation days 9-18 (B mice), and were tested at adulthood for behavioral changes. B mice showed deficits in the eight-arm maze, a behavior related to the septohippocampal pathways. Consequently, transplantation of septal (mostly cholinergic) and locus coeruleus (mostly noradrenergic) neurons was applied to reverse the behavioral deficits. Most (75%) of the controls but none of the B mice reached a specific criterion in the eight-arm maze. However, transplantation of fetal septal tissue into the hippocampus of B mice enabled 55% of them to reach criterion. Transplantation of locus coeruleus tissue did not improve the performance of B mice. The viability of the transplants was confirmed in cytochemical studies. The results suggest that transplantation of neurons can be applied to reverse phenobarbital-induced behavioral birth defects.
Mice were exposed to phenobarbital prenatally (B offspring) by feeding their mother 3 g/kg phenobarbital in milled food on gestation days 9-18; control dams received unadulterated milled food. At age 50 days, B offspring had fewer fluorescing noradrenergic (NE) cells in the locus coeruleus than control (P less than 0.001). Hippocampal NE levels were also lower in B than in control offspring, while the cerebellar NE levels of B offspring remained normal. Since B offspring are known to be deficient in their hippocampal eight-arm maze behavior, an attempt was made to reverse the behavioral deficit by transplantation of normal embryonic locus coeruleus NE cells into the impaired hippocampus of B offspring. While sham and NE-transplanted controls needed approximately 2 days to reach criterion in the maze, sham-transplanted B required approximately 5 days to reach criterion (P less than 0.01). The scores of NE-transplanted B mice were similar to B and differed significantly from control (P less than 0.01). Thus, it appears that the hippocampal behavioral deficits studied may not be related to alterations in locus coeruleus-hippocampal NE innervations.
Zinc and iron levels were studied in mice with early (pre/neonatal) exposure to phenobarbital, as the levels of these trace metals are known to be correlated with specific behaviors shown in our previous and present experiment to be affected by early phenobarbital administration. Mice were exposed to phenobarbital prenatally or neonatally. At adulthood they showed marked reduction from control in all parameters of eight-arm maze performance (P less than 0.001). Since zinc is known to be correlated with this behavior, it was subsequently studied in barbiturate exposed animals. The differences between barbiturate exposed and control offspring for zinc levels in plasma, brain and hippocampus did not reach statistical significance. Our previous studies have shown that the number of dopamine receptors and the resulting apomorphine-induced climbing behavior is altered after early exposure to phenobarbital. The effect of iron level on dopamine receptors is now well established. Subsequently, a group of mice were tested for iron levels in their brain and liver. No significant differences were found. It is suggested that deficits in the hippocampal behaviors, mainly eight-arm maze, after early exposure to phenobarbital are not related to changes in zinc levels. Similarly, early phenobarbital-induced alternation in dopamine receptors and the resulting dopaminergic behaviors are not related to changes in iron levels.
Pregnant women with high estrogen levels were more sensitive to barbiturate-induced narcosis and hypothermia than nonpregnant and postmenopausal women. Within each group, there was a negative correlation between estrogen level and decreased sensitivity to barbiturates. It appears that estrogen alters resistance to barbiturates through its effect on the activity of dopamine receptors.
Treatment with DES one hour prior to pentobarbital injection resulted in diminution of the narcotic sleep and hypothermia usually found after pentobarbital (50 mg/kg 1) injection in male mice. The effect was biphasic: significantly countered relative to saline pretreated controls at low (.001-.10 mg/kg 1) and at high (10-50 mg/kg -1) DES doses only. Giving DES alone did not change core body temperature compared to saline injected controls, at either 25 degrees C or at 33 degrees C. At 33 degrees C, neither PeB narcosis nor body temperature loss was significantly inhibited by DES. Possible cytoplasmic, nonsex differentiated bases for these estrogen effects on barbiturate action in the brain is discussed.
The Q-tip test was applied on 105 patients. Fifty-one had stress urinary incontinency (SUI), 28 had bladder instability by clinical and urodynamic criteria, and 36 had mild or moderate pelvic relaxation without urinary pathology. More than 90% of the patients with SUI and no previous surgery had a positive Q-tip test, with 90% test sensitivity in this group. More than one-third of the patients with bladder instability and almost one-half of the patients with pelvic relaxation and no urinary incontinence had a positive Q-tip test, for low test specificity. The Q-tip test is a simple clinical tool for diagnosing pelvic relaxation, which at times leads to SUI. Almost all patients with primary SUI have pelvic relaxation. The Q-tip test alone does not stand as a diagnostic test. When it is positive, the diagnosis of genuine stress incontinence is possible although not absolute. A negative test should cause one to question the diagnosis of genuine stress incontinence, and sophisticated and more expensive tests should be ordered before establishing a final diagnosis.
Treatment of mice with haloperidol increased the number of dopamine D2 receptors (Bmax). The animals were given 40 or 50 mg of pentobarbital. Animals treated with haloperidol had a shorter duration of narcosis induced by pentobarbital than the controls, suggesting a decreased sensitivity to pentobarbital which was functional (CNS), since the animals treated with haloperidol had higher levels of pentobarbital in the brain upon awakening than the controls. The results suggest that increased Bmax reduces the sensitivity of the brain to pentobarbital.
The present experiment was designed to study the sensitivity of dopamine (DA) receptors after early (pre- and neonatal) administration of phenobarbital (PhB). These receptors have been implicated in some of the behaviors which are altered by early barbiturate exposure. Pregnant HS mice were exposed to PhB (3 g/kg milled food) from the 9th to the 18th day of gestation. Their offspring were the subjects of the prenatal studies. The neonatal treatment consisted of daily injections of PhB to pups from ages 2 to 21 days (50 mg/kg PhB). Striata of treated animals and controls from both treatments, prenatal (PreB) and neonatal (NeoB) were removed at 22 or 50 days for DA receptor binding assay. Using Scatchard plot analysis of [3H]spiroperidol specific binding, long-term increase from control level in DA receptor number (Bmax) was found in the PreB mice, while NeoB mice had decreased Bmax (P less than 0.001). No differences were found in the respective KD values. In parallel psychopharmacological studies, PreB mice had increased apomorphine-induced climbing behavior response, and in previous studies we showed that NeoB had decreased apomorphine induced-climbing behavior response. The long-term alterations in DA receptor number may possibly mediate the changes in brain sensitivity to barbiturate and alcohol found in our previous studies.
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