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R H Fishman

Publications and source records attributed to R H Fishman.

30 records · Page 2Linked to original sources
PubMed1989

Correlated ultrastructural damage between cerebellum cells after early anticonvulsant treatment in mice.

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.

Animals↗
PubMed1987

Regional brain superoxide dismutase activity is altered differently by heat in warm and cool mice.

The significant regional variation in brain superoxide dismutase (SOD) activity was similar in mice from both warm and cool cohorts. Mice in the cool cohort generally had higher SOD activity, which varied significantly with body temperature in striatum and in preoptic area of the hypothalamus. Changes in SOD activity following heating were revealed only when warm and cool cohorts were analysed separately. SOD activity decreased significantly in striatum, hypothalamus, and hippocampus of the cool cohort only. The decline was to levels consistent with those of the warm cohort. Body temperature of cool mice increased more than that of warm mice following each increment of heating so resultant body temperatures became similar. The role of SOD as part of a differential defense against heat stress in warm and cool mice is presented.

Animals↗
PubMed1987

Diethylstilbestrol counteracts barbiturate narcosis and hypothermia in male mice.

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.

Animals↗
PubMed1986

The effect of intragastric administration of delta 9-tetrahydrocannabinol on the growth and development of fetal mice of the A/J strain.

Pregnant A/J mice were intubated with vehicle (sesame oil:Tween 80:water) or 60, 120, or 240 mg/kg of delta 9-tetrahydrocannabinol on Days 11 and 12, 12 and 13, or 13 and 14 (vehicle and 240 mg doses only) of gestation. Mice were killed on Day 20 of gestation, and examined for number of corpora lutea and live and resorbed fetuses. Fetuses were weighed and examined for gross external and internal malformations. Each treatment group consisted of a minimum of 10 litters with about 10 pups per litter. In a few groups the effects of feed deprivation on Day 12 or of glucocorticoid administration on Days 12 and 13 (positive control) were assessed. Intubation with vehicle or delta 9-tetrahydrocannabinol, or feed deprivation did not affect number of live fetuses, incidence of resorption, fetal weights, or gross malformations other than cleft palate. Intubation of delta 9-tetrahydrocannabinol on gestational Days 12 and 13 or 13 and 14 increased the mean frequency of cleft palate formation. The increase was 2- to 2.5-fold at the 240-mg dose, being significant (p = 0.05) in the Days 12 and 13 group. Cortisone acetate and corticosterone injection induced both resorption and cleft palate formation. Other developmental or reproductive parameters were not influenced by delta 9-tetrahydrocannabinol treatment. We conclude that delta 9-tetrahydrocannabinol administered by gavage during Days 12 and 13 of gestation retards normal palatal development.

Administration, Oral↗
PubMed1984

Ascorbic acid effect on ethanol sensitivity via possible dopaminergic mediation.

Mice were injected with 0, 107, 215, 430, or 1720 mg/kg of ascorbic acid. Thirty min later they were tested for ethanol (3.5 g/kg) induced sleep time. Brain ethanol levels were determined upon awakening. Another group of mice were tested for apomorphine (3 mg/kg) induced locomotor activity also 30 min after ascorbic acid injection. Ascorbic acid in doses above 215 mg/kg augmented ethanol sleep time up to 210% at the highest doses, the increase being significant from 430 mg/kg. Brain ethanol levels upon awakening were reduced by ascorbic acid treatment; this reduction was significant at 1720 mg/kg dose. Ascorbic acid decreased apomorphine-induced locomotor activity in a dose response manner that paralleled the ascorbic acid increase of ethanol sleep time. At the highest dose of ascorbic acid, apomorphine-induced locomotor activity was completely eliminated. It is suggested that ascorbic acid increases brain sensitivity to ethanol by lowering the activity of dopamine receptors.

Animals↗
PubMed1983

Ultrastructural evidence of long-lasting cerebellar degeneration after early exposure to phenobarbital in mice.

Previous studies in this laboratory demonstrated a 20 to 30% reduction in cerebellar Purkinje and granule cells after exposure to phenobarbital (PhB) early in life. Therefore, neurons in the cerebellar cortex were examined for signs of cytologic degeneration using transmission electron microscopy (TEM) after exposure to PhB pre- and postnatally. Pregnant mice were given the acid form of PhB in their milled food (3 g/kg, gestation days 9 to 18) and water, ad libitum. Neonates were injected s.c. with an aqueous solution of sodium PhB (50 mg/kg body weight), days 2 to 21 after delivery. Controls were fed regular food or injected with the vehicle. The offspring were anesthetized on day 14 or 50 by an acute overdose of PhB and immediately perfused with a formaldehyde-paraformaldehyde or glutaraldehyde solution. The pyramis vermis of the cerebellar cortex was excised and processed routinely for TEM. The three layers of the cortex were examined. A short-term effect (at day 14) was found. More significantly, the treatment appeared to establish or trigger a degenerative process, the results of which were still apparent at day 50, more than 30 days after the termination of PhB treatment. Using double-blind evaluation for the presence and frequency of abnormalities, the cerebellar neurons of treated animals had 155 to 300% more abnormalities compared with control animals. Abnormalities included (i) Mitochondrial degeneration, ranging from swelling, collapse of cristae, vacuolization, to total granularization; (ii) lamellar bodies distributed throughout the cytoplasm and in cell processes; and (iii) myelin sheath degeneration, including periodic swelling and collapse, twisting of the coat, and scattered, unevenly stained areas. Damage was usually focal. Affected cells were found adjacent to normal cells in all areas of the cortex. PhB may cause the neural damage through a possible hormonal role.

Animals↗
PubMed1983

Long-lasting effects of early barbiturates on central nervous system and behavior.

Forty years of prescribing barbiturates to pregnant women and infants, and thirty years of animal research have shown that barbiturates affect the developing central nervous system (CNS) and behavior. This paper compiles and reviews animal and selected human literature in this research area. Early barbiturate exposure in animals reduces brain weight with related changes in brain biochemistry and neuromorphology. Significant changes may be found in surviving adult offspring. Evidence of CNS and behavioral damage in human beings due to early barbiturate exposure is not clearcut, however, confounded by the conditions for which the drugs are prescribed. In animals, early drug exposure significantly reduces levels of hormones, vitamins, and other biologically active macromolecules via (long-lasting) induction of hepatic metabolizing enzymes. Whether or not in humans treated with barbiturates, hormone levels remain within the normal range (by-feed-back regulation) and, also, if vitamin deficiencies can be simply corrected by supplements is still being debated. Early barbiturates administered to animals is associated with long-lasting disturbances in activity, learning performance, sexual behavior, and reproductive function, but not in a simple dose-exposure related manner. Animal studies show that long-lasting functional tolerance to drugs develops following early barbiturate exposure. Although infants become "passively addicted" following in utero exposure, there is as yet no data on subsequent development of human adult tolerance. Drug related damage must, in any case, be weighed against therapeutic benefits of drug administration and the results of failure to treat.

Animals↗
PubMed1982

Early barbiturate treatment eliminates peak serum thyroxine levels in neonatal mice and produces ultrastructural damage in the brains of adults.

Serum thyroxine levels peak sharply at the end of the second postnatal week in mice. Treating neonatal mice with barbiturates (PhB) completely eliminates this marked thyroxine (T4) peak without significantly affecting nonpeak levels at other ages. PhB treatment at this same time also establishes or induces long-lasting degenerative processes that continue to result in ultrastructural neural deficits in adults, long after treatment has been discontinued. Similar neural deficits have been observed in animals which were deficient in T4 during this same period of development.

Aging↗
PubMed1982

Mechanisms of dopamine antagonism by morphine in rodents.

A number of investigators have concluded on the basis of a substantial and compelling body of biochemical, pharmacological and behavioral evidence, that opiates and particularly morphine, directly block central dopamine (DA) receptors. This evidence includes the recent finding that cataleptogenic doses of morphine suppress 3H-spiroperidol binding to striatal membranes ex vivo. On the other hand, an important albeit relatively sparse literature of experimental evidence exists suggesting that morphine and other mu-receptor opiates do not directly bind to central dopaminergic receptors. The most convincing evidence to this effect are behavioral findings that morphine potentiates rather than inhibits the stereotyped behavior induced by the direct DA agonist apomorphine and biochemical evidence demonstrating a failure of 3H-morphine or 3H-dihydromorphine to specifically bind central DA receptors in striatal tissue. (Indeed, even those reports that demonstrated a morphine induced suppression of 3H-spirioperidol labelling of DA receptors failed to find a direct effect on post-synaptic receptors.) Evidence is presented in this report to show that morphine acts presynaptically to acutely inhibit DA release, and thus, that morphine inhibition of DA receptor mediated responses is indirect, being the result of an inhibition of pre-synaptic DA release rather than a direct effect exerted on post-synaptic DA receptors themselves.

Animals↗
PubMedDate not supplied

Lessened sensitivity to apomorphine induced climbing behavior in mice following neonatal exposure to phenobarbital.

Heterogeneous HS/Ibg mice were injected daily with 50 mg/kg phenobarbital (PhB) from age 2 to 21 days (B group), while control litter mates received vehicle injections. Control and a B mice were then tested for striatal climbing behavior induced by 2 or 5 mg/kg apomorphine, at ages 22, 28, 35 or 44 days. At age 22 days B mice had reductions of climbing from control levels of 44% and 41% for 2 and 5 mg apomorphine respectively (p less than 0.01), regardless of sex differences. On day 28 the respective reductions were 16% and 32% (p less than 0.05). The differences on days 35 and 44 were small and did not reach statistical significance. Since climbing has been found to be induced primarily by postsynaptic striatal dopaminergic receptors, it is suggested that neonatal exposure may reduce the behaviors mediated by striatal postsynaptic dopamine receptors. The present findings support other studies implicating postsynaptic striatal dopamine receptors in the behavioral alterations induced by early PhB exposure.

Animals↗