Biomedical subjects
R L Isaacson
Publications and source records attributed to R L Isaacson.
Cellular alterations produced by the experimental increase in intracellular calcium and the nature of protective effects from pretreatment with nimodipine.
The immortalized septal cell line, SN56 B5 G4, generated by the fusion of mouse septal area cells and neuroblastoma cells, was used to determine if nimodipine, an antagonist of voltage sensitive calcium 'L' channels, might act in a neuroprotective fashion when intracellular calcium levels were raised by incubation in ouabain and monensin. Fluorescent indicator dyes and the automated spectrofluorometer, the CytoFluor 2300, were used to analyze specific cellular targets and functions affected by ouabain and monensin and possible protection by prior incubation with nimodipine. Ouabain and monensin were used together to create a time- and dose-dependent toxic episode. Increases in the emission intensity of Fluo3-AM demonstrated that the concentration of intracellular calcium was monotonically increased by increasing levels of ouabain-monensin. The calcein-AM fluorescent probe indicated that there were no changes in plasma membrane permeability during the toxic episode. Lysosomal integrity decreased as indicated by decreases in neutral red retention. The concentration of free radicals increased as shown by the increase in emission intensity of 2',7'-dichlorfluorescein. Nimodipine pretreatment of the cells incubated with ouabain and monensin resulted in apparent protection of lysosomes and a reduction in the level of free radicals. While nimodipine, by itself, produced a small decrease in intracellular calcium, it actually augmented the ouabain-monensin induced increase in intracellular calcium. The data suggest that in immortalized septal cells, (a) nimodipine offers protection to certain of the responses induced by ouabain-monensin, (b) the protection offered by nimodipine may be independent of antagonism of voltage sensitive calcium channels, and (c) that the protective changes can occur at the same time that intracellular calcium is increasing. These latter observations question the hypothesis that the protection against cell death and dysfunction offered by nimodipine is due solely to maintaining calcium homeostasis.
Behavioral and anatomical consequences of unilateral fornix lesions and the administration of nimodipine.
Male Wistar rats subjected to unilateral fimbria-fornix transection by mechanical knife cut or to sham operations were tested in a water maze and in an open field. Half the animals in each group were treated with either 0.06 mg/kg nimodipine or vehicle, administered i.p. for 7 days, beginning the day of surgery. Animals were sacrificed and brains were processed for acetylcholine esterase (AChE) histochemistry. In the water maze, lesioned rats showed a significant impairment relative to the sham-operated animals. Nimodipine treatment did not improve performance. There were no differences among the groups in the observed frequencies of the open field behaviors of locomotion, hole-poke, rearing and grooming. A significant reduction of AChE-positive cell bodies was found in the medial septal region on the side of the lesion. There were no differences in water maze performance among groups of rats treated with 0.0, 0.5, 1.0, or 5.0 mg/kg nimodipine for 7 days, beginning the day of fimbria-fornix transection, in an attempt to determine any dose-dependent effect of the drug.
Actions and interactions of calcium modulators and ethanol on rat atrial membrane potentials.
The effects of ethanol and dihydropyridines on atrial membrane potentials (MP) were studied. Rat atrial strips superfused with Tyrode's solution (36 degrees C) were driven at 5 Hz while recording MP with intracellular microelectrodes. Bay K 8644 7 X 10(-7) M (BAYK) increased the amplitude of the action potential (AAP) without affecting the resting membrane potential (RMP) or the Vmax of phase 0 (Vmax 0). The velocity of change in voltage decreased at the beginning of the repolarization, causing an increase in the action potential duration (APD), but it was not modified at negative voltages. Nimodipine 4.2 X 10(-6) M reduced the AAP without affecting RMP or Vmax 0. The velocity of change in voltage increased at the beginning of the repolarization, causing a decrease in the APD, but was not modified at negative voltages. Ethanol 5.3 X 10(-2) M exerted actions similar to those of nimodipine. Simultaneous exposure to ethanol and nimodipine resulted in changes not different from those obtained with each of the two compounds. The MP remained unchanged when the preparations were exposed to ethanol and BAYK simultaneously. In summary, ethanol and nimodipine exerted similar actions on the atrial MP while BAYK had opposite actions. The effects of ethanol and BAYK cancelled each other.
Inotropic effects of ethanol and dihydropyridines on the guinea pig heart atrial muscle.
The effects of ethanol and/or dihydropyridines (DHPs) on force of contraction of atrial muscle were studied. Guinea pig atrial strips superfused with Tyrode's solution (36 degrees C) were driven (1.5 Hz) while recording muscle tension. Bay K 8644 (BAYK) increased, while nimodipine or ethanol reduced, the peak tension developed and the maximum velocity of development of tension. The effects of ethanol were readily reversible, but those of the DHPs were not. The combined actions of ethanol and DHPs were the result of the synergism or antagonism of the drugs tested. The shorter duration of the action of ethanol resulted in the effect of DHPs being still evident well after the exposure to the drugs ended. In summary, ethanol and nimodipine exerted depressant actions on atrial contractile force, while BAYK had opposite effects. The different mechanisms of action may explain the different duration of the effects of ethanol (physical agent) and DHPs (receptor-binding chemicals).
Regional changes in 2-deoxyglucose uptake after neocortical and hippocampal destruction.
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Intracerebral adrenocorticotropic hormone mediates novelty-induced grooming in the rat.
Intact male rats exhibited more grooming in unfamiliar testing chambers than in their home cages. Hypophysectomized rats showed a much reduced increase in grooming in these testing chambers. Intraventricular injections of antiserum to adrenocorticotropic hormone to intact rats decreased the grooming usually observed in the novel situation, whereas a similar injection of control serum did not produce this effect. Peripheral injections of the antiserum did not affect grooming. Since intraventricularly injected adrenocorticotropic hormone induces excessive grooming, these results suggest that the increased grooming observed in the novel environment may be at least partly due to the release of this hormone directly into the cerebral ventricular system.
Stretching and yawning: a role of glutamate.
Systemic injection of GDEE (glutamate diethyl ester), an antagonist of glutamate and aspartate receptors, induces stretching and yawning in rats. This was not accompanied by excessive grooming. Coupled with previous work these findings give evidence that a glutamatergic mechanism is involved in stretching and yawning.
Naloxone and haloperidol reduce grooming occurring as an aftereffect of novelty.
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The influence of brain damage on locomotor behavior of mice selectively bred for high or low activity in the open field.
Locomotor activity was measured in mice with lesions restricted to the neocortex, in animals with hippocampal damage, and in sham-operated control mice of the selectively bred high and low open-field activity lines developed by J. C. DeFries. Postoperatively, the high-activity animals with hippocampal lesions showed reduced activity relative to those with only neocortical damage, and their postoperative activity levels were uncorrelated with those obtained preoperatively. Testing the animals under reduced illumination enhanced locomotor activity, with the greatest increase demonstrated by high-activity mice with hippocampal damage. While increases in activity under low illumination did occur in the low-activity line, no significant group differences were observed. Amphetamine did not affect locomotor behavior of the high-activity control animals, whereas doses of 1.0 and 10.0 mg/kg reduced the activity of the low-activity mice. High-activity mice with hippocampal damage evidenced a significant increase in locomotor behavior after the 10.0 mg/kg dose. These results emphasize that the behavioral effects of brain lesions and pharmacological manipulations cannot be adequately assessed without regard to genotype of the animals under investigation.
The development of responsiveness to dopaminergic agonists.
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Studies of kainate-induced wet-dog shakes in the rat.
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Repeated intraventricular injections of ACTH 1-24: the effects of home or novel environments on excessive grooming.
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Dopamine agonists: their effect on locomotion and exploration.
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The effect of ACTH1-24 on locomotion, exploration, rearing, and grooming.
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The development of food search behavior by rats: the effects of hippocampal damage and haloperidol.
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Clonidine sensitivity in the developing rat.
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Deficient brain development following colcemid treatment in postnatal rats.
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