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L B Flexner

Publications and source records attributed to L B Flexner.

At least 37 records · Page 2Linked to original sources
PubMed1977

Dose-response relationships in attenuation of puromycin-induced amnesia by neurohypophyseal peptides.

Intracerebral injections of puromycin one day after training of mice in a Y-maze cause amnesia when the animals are tested 7 days later. This amnesia was shown to be attenuated by various neurohypophyseal hormones, analogs and fragments, administered subcutaneously immediately after training. Dose-response relationships have been obtained for the attenuation of puromycin-induced amnesia in mice by selected neurohypophyseal peptides. All of the compounds tested reduce the amnesia in a dose-related way, suggesting that these peptides may interact with specific receptors to induce their central effect. Among the peptides studied the two most potent--i.e., those that cause substantial retention of memory at the lowest doses--are the neurohypophyseal hormone arginine vasopressin and Z-prolyl-leucyl-glycinamide (Z-MIF).

Amnesia↗
PubMed1976

Effect of two inhibitors of dopamine beta-hydroxylase on maturation of memory in mice.

Bitemporal injections of puromycin that primarily affect the hippocampal-enthorhinal cortical areas suppress memory of maze-learning in mice for 3 days after training but are ineffective 6 or more days after training. At these later times, injections affecting widespread areas of the brain in addition to the hippocampal-entorhinal area are necessary for amnesia. These observations are interpreted to indicate that the locus of the memory trace has enlarged at 6 days to include other parts of the central nervous system in addition to the hippocampal-entorhinal area. To produce an imbalance of neurotransmitters and so to test their importance in enlargement of the memory trace's locus, we treated mice for 7 days after training with inhibitors of dopamine beta-hydroxylase. These mice, unlike untreated controls, developed amnesia after bitemporal injections of puromycin. In view of additional control experiments, we interpret these results to suggest that an imbalance of transmitters suppresses the normal enlargement of the locus of the memory trace.

Animals↗
PubMed1976

Comparison in mice of the amnestic effects of cycloheximide and 6-hydroxydopamine in a one-trial passive avoidance task.

To test further the hypothesis that cycloheximide (CXM)-induced amnesia is due in part to its effects on the central adrenergic system, a comparison was made in mice of the effects of the antibiotic and of 6-hydroxydopamine (6-OHDA) on memory of a one-trial passive avoidance task. Both drugs produced anmesia 24 hr after training but unlike CXM, 6-OHDA had no effect on memory 20 min after training.

Animals↗
PubMed1975

Neurohypophyseal hormones, analogs, and fragments: their effect on puromycin-induced amnesia.

Neurohypophyseal hormones and several of their analogs, as well as N-terminal and C-terminal fragments, have been studied for their ability to attenuate puromycin-induced amnesia in mice. [8-Lysine]vasopressin, [8-arginine]vasopressin, and the analogs des-9-glycinamide-[8-lysine]vasopressin, [1-beta-mercaptopropionic acid, 8-lysine]vasopressin, [1,6-aminosuberic acid, 8-lysine]vasopressin, [4-leucine, 8-lysine]vasopressin, glycyl-glycyl-glycyl-[8-lysine]vasopressin, [1-beta-mercaptopropionic acid, 8-D-arginine]vasopressin, and [1,6-aminosuberic acid, 8-arginine]vasopressin are active. [8-Arginine]oxytocin as well as oxytocin and all of its other analogs tested are inactive with the striking exception of glycyl-glycyl-glycyl-oxytocin. The structural aspects of the neurohypophyseal hormones which appear to be important for significant activity in memory consolidation include the combination of a cyclic moiety containing the Tyr and Phe residues along with a basic residue in position 8. Another series of active compounds comprises C-terminal neurohypophyseal peptides and analogs thereof, including the naturally occurring Pro-Leu-Gly-NH2 and, most surprisingly, Leu-Gly-NH2, as well as its derivatives D-Leu-Gly-NH2 and the diketopiperazine, cyclo(-Leu-Gly-).

Amnesia↗
PubMed1975

Studies on memory: inhibitors of protein synthesis also inhibit catecholamine synthesis.

The rates of accumulation of newly synthesized catecholamines and endogenous catecholamine levels in mice were determined after treatment with cycloheximide, acetoxycycloheximde, puromycin, and anisomycin. The rates of accumulation were found to be decreased by all antibiotics tested, weakening the assumption that their amnestic effects are due solely to inhibition of protein synthesis.

Animals↗
PubMed1975

The effect of acetoxycycloheximide on rate of accumulation of cerebral catecholamines from circulating tyrosine as related to its effect on memory.

The rate of accumulation of newly synthesized catecholamines and endogenous catecholamine levels in mice were determined after an amnestic intracranial dose of acetoxycycloheximide. Rates of accumulation were found to be severly decreased for a period of 12 hr after injection. Total catecholamine levels were increased from 1 to 4 hr, then decreased 17 hr following injection. These results are discussed in terms of previous behavioral observations. It is pointed out that they weaken the assumption that acetoxycycloheximide's amnestic effects are solely due to inhibition of protein synthesis.

Animals↗
PubMed1973

Cycloheximide and acetoxycycloheximide: inhibition of tyrosine hydroxylase activity and amnestic effects.

Mice and rats trained after treatment with cycloheximide or acetoxycycloheximide in a conditioned avoidance response develop an amnesia of their training experience. This amnesia has been attributed to the profound inhibition of protein synthesis caused by the two antibiotics. Evidence is presented that additionally the antibiotics inhibit the activity of tyrosine hydroxylase, a finding that suggests that their amnestic effect may be due in part to reduction of the functional pool of norepinephrine.

Acetates↗
PubMed1972

Acetoxycycloheximide-induced transient amnesia: protective effects of adrenergic stimulants.

It has previously been shown that rats trained 5 hr after intracerebral injection of acetoxycycloheximide show a transient amnesia at 24 hr after training. We have tested the possibility that adrenergic stimulants might provide protection from the amnesia. Metaraminol, given either before or after training or before testing, prevents the drug-induced amnesia. D-Amphetamine, injected soon after training, also prevents the amnesia. A model is presented to explain the drug-induced amnesia in terms of both the assumed effect of acetoxycycloheximide on the adrenergic system and prevention of the amnesia by metaraminol and D-amphetamine.

Acetates↗
PubMed1972

Effect of corticotropin and desglycinamide 9 -lysine vasopressin on suppression of memory by puromycin.

The puromycin-induced blockade of expression of maze learning in mice can be prevented by subcutaneous administration of "Purified Cortrophin Gel" up to 3 days prior to training. A similar protective effect was not found when highly purified corticotropin was tested, but was observed after administration of desglycinamide(9)-lysine vasopressin. It appears that pressorpeptides are more potent protective agents than corticotropin when administered subcutaneously, and that vasopressin contamination of the commercial preparation was probably responsible for the protective effects previously reported. These experiments suggest that vasopressin and its congeners modify memory consolidation in such a way that the "expression" of memory becomes insensitive to puromycin.

Adrenocorticotropic Hormone↗
PubMed1971

Studies on memory: distribution of peptidyl-puromycin in subcellular fractions of mouse brain.

Previous experience has led us to suggest that sustained blockage of memory in mice upon administration of puromycin is caused by the persistence of peptidyl-puromycin at synapses. The block can be removed and memory restored by intracerebral injections of water and by subcutaneous or intraperitoneal injections of several psychotropic drugs. The present experiments provide evidence that peptidyl-puromycin persists for long periods in subcellular fractions of synaptosomes (nerve endings), and that the peptide is lost from synaptosomal, but not from mitochondrial, fractions when memory is restored. These findings strengthen our interpretation of the mode of action of puromycin on memory.

Acetylcholinesterase↗
PubMed1971

Pituitary peptides and the suppression of memory by puromycin.

It has previously been shown that the expression of memory of maze-learning in mice is blocked by intracerebrally-injected puromycin one or more days after the training experience, and that bilateral adrenalectomy before training protects memory against this effect of puromycin. Purified cortrophin gel, injected subcutaneously up to 3 days before training, has now been found to give results like those obtained with adrenalectomy and, additionally, to provide a high degree of protection when injected up to 16 hr after training. Several possible explanations for these effects have been considered and found to be inadequate.

Adrenalectomy↗
PubMed1970

Adrenalectomy and the suppression of memory by puromycin.

It has previously been shown that expression of memory of maze-learning in mice is blocked by puromycin injected intracerebrally one or more days after the training experience. Bilateral adrenalectomy before training has now been found to protect memory against the effects of puromycin. This protection is absent when adrenalectomy follows training. In view of control experiments, we conclude that adrenalectomy before training modifies factors necessary for the expression of memory and that this alteration makes puromycin ineffective in blocking memory.

Adrenal Glands↗
PubMed1970

Some evidence for the involvement of adrenergic sites in the memory trace.

Puromycin was injected bitemporally in mice one day after training in a Y-maze. Eight days later various psychotropic drugs were injected intraperitoneally or subcutaneously at maximum tolerable doses. Ten days after the drug injection the mice were tested for their memory of the maze-learning. Memory was lost in control animals injected with saline but restored in most of the animals injected with imipramine, tranylcypromine, or D-amphetamine. Some indication of restoration was observed after injection of reserpine or L-dopa. These results suggest that the blockage caused by puromycin is due to adsorption of peptidyl-puromycin to adrenergic sites and that these sites may be involved in the memory trace.

Animals↗
PubMed1969

Puromycin: effect on memory of mice when injected with various cations.

Puromycin dihydrochloride neutralized with bases of potassium, lithium, calcium, or magnesium fails to block expression of memory of maze learning in mice, unlike puromycin neutralized with NaOH. This failure may be due to cationic binding at anionic membrane sites with a resultant exclusion of sufficient peptidyl-puromycin to make it ineffective in blocking memory.

Animals↗
PubMed1968

Puromycin: action on neuronal mitochondria.

Puromycin, in dosages that inhibit cerebral protein synthesis and expression of memory in mice, produces swelling of neuronal mitochondria. Acetoxycycloheximide, which inhibits cerebral protein synthesis to the same extent as puromycin, fails to produce swelling of neuronal mitochondria. Puromycin and heximide mixtures produce severe inhibition of protein synthesis, but result in a minimal swelling of neuronal mitochondria and in a decrease of peptidylpuromycin complexes to a level of 30 percent of that following the injection of puromycin alone. It is concluded that swelling of neuronal mitochondria in the presence of puromycin is not due to inhibition of cerebral protein synthesis per se, but is related to a specific action of puromycin on ribosomal protein synthesis. The findings are consistent with the hypothesis that peptidyl-puromycin complexes are responsible for mitochondrial swelling.

Animals↗
PubMed1968

Intracerebral saline: effect on memory of trained mice treated with puromycin.

It was shown that puromycin administered to mice 1 or more days after maze-learning blocks expression of memory; the blockage can be removed by intracerebral injections of saline. We present evidence that intracerebral injections of saline are relatively ineffective in restoring memory when puromycin is administered either before or immediately after training; in these two situations puromycin appears to interfere with consolidation of memory.

Amnesia↗