Biomedical subjects

L B Flexner

Publications and source records attributed to L B Flexner.

At least 19 recordsLinked to original sources

PubMed1995

Complementary memory storage sites in mice: their development as affected by the competitive NMDA receptor antagonist, CPP.

Bitemporal injections of puromycin consistently induce amnesia of aversive maze learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we conclude that in our experimental paradigm, complementary memory storage sites normally develop in additional cerebral areas within 6 days following training. Previous experiments have indicated that the central adrenergic and cholinergic systems are critically involved in this process. We now present evidence that administration of the NMDA receptor antagonist, CPP, blocks the development of these complementary memory storage sites. As suggested by studies of long-term potentiation, NMDA receptor-dependent postsynaptic calcium appears to be essential for the development of these storage sites and indeed to trigger their development.

Amnesia↗

PubMed1992

Long-term suppression of the development of complementary memory storage sites in mice: functional interdependence of acetylcholine and dopamine.

Bitemporal injections of puromycin consistently induce amnesia of aversive maze learning in mice when given within 3 days after training. These injections consistently fail to induce amnesia when given 6 or more days after training. Consistent with the evidence from other laboratories, we interpret these results to indicate that the initial, temporal memory storage sites are supplemented 6 days after training by the development of complementary storage sites in other cerebral areas. Previous experiments have shown that this process is suppressed for 30-60 days by a single SC injection of scopolamine, a muscarinic antagonist. We now find that this suppressive action of scopolamine can be completely nullified by haloperidol, a dopaminergic antagonist. This finding supports the view that there may be a therapeutic role for dopamine antagonists in the treatment of cognitive dysfunction associated with cholinergic loss.

Acetylcholine↗

PubMed1991

Long-term suppression in mice of the development of complementary memory storage sites: effect of a muscarinic antagonist.

Amnesia↗

PubMed1989

Long-term suppression of the cerebral spread of a memory: effects of idazoxan and clonidine.

Bitemporal injections of puromycin consistently induce amnesia of aversive maze-learning in mice when administered within 3 days of training. These bitemporal puromycin injections lose their amnestic effectiveness if the latency between training and injection is extended beyond 6 days. Consistent with other evidence, we believe that memory (in our task) "spreads" during the 6 days following training. Since previous experiments have indicated that the central noradrenergic system is involved in this process of "memory spread," we have examined the effect of stimulation or blockade of the alpha 2-receptor. To this end, we administered a single dose of the alpha 2-adrenoceptor antagonist, idazoxan, or the alpha 2-agonist, clonidine. Idazoxan (1 mg/kg, SC) had no effect on engram spread. Clonidine (25 micrograms-125 ng/kg, SC), by contrast, suppressed engram spread for at least 30 days after treatment. When mice were tested at 60 and 90 days after treatment, spontaneous recovery (i.e., engram spread) was evident in only about 50% of the clonidine treated mice. Coadministration of idazoxan with clonidine blocked the effects of clonidine on "memory spread."

Animals↗

PubMed1985

Visual discrimination learning and interhemispheric transfer in the cat, as affected by 6-hydroxydopamine.

Learning and interhemispheric transfer of visual flux, pattern and form discriminations were studied in the cat after selected exposure of one suprasylvian cortex to 6-hydroxydopamine (6-OHDA). Biochemical assay using High Performance Liquid Chromatography (HPLC) two weeks after 6-OHDA revealed no discernible norepinephrine or dopamine in the treated cortex, but elevated concentrations of these transmitters in the cortex of the opposite hemisphere. Visual discriminations learned before treatment with 6-OHDA were retained at a high level using either the eye on the side of chemical lesion or the eye on the untreated side. An asymmetric deficit in learning new form discriminations was present, however, when the eye on the untreated side was used, in contrast to normal learning using the eye on the side of the hemisphere with depleted adrenergic nerve supply. Once learning was achieved using the lesioned hemisphere transfer of the engram was found to the untreated hemisphere. Thus, the unlesioned hemisphere was unable to learn normally using direct retinal input from the ipsilateral eye, but showed good capacity for learning using indirect visual input from the contralateral eye. This suggests a powerful influence of the callosum on the learning abilities of the two hemispheres, an influence proved by sectioning the callosum. Callosotomy resulted in a reversal of the discriminative capacities seen after 6-OHDA, i.e. the lesioned hemisphere was defective relative to the unlesioned hemisphere.

Animals↗

PubMed1985

Blockade of peripheral beta-adrenergic receptors fails to suppress the cerebral spread of an engram in mice.

Using bitemporal injections of puromycin, we have reported observations interpreted to indicate that a systemic injection of (-)-propranolol (50 micrograms/kg) drastically suppressed the spread of an engram in mice from the hippocampalentorhinal area to widespread cerebral areas. The present experiments were made with a non-selective, irreversible beta-adrenergic receptor antagonist that fails to cross the blood-brain barrier in order to test the possibility that the propranolol-induced blockade of peripheral beta-receptors might contribute to its effect on engram spread. Prolonged blockade of peripheral receptors by the irreversible antagonist had no effect on engram spread, suggesting that propranolol's effect was centrally mediated.

Animals↗

PubMed1985

Blockade of beta 1- but not of beta 2-adrenergic receptors replicates propranolol's suppression of the cerebral spread of an engram in mice.

Bitemporal injections of puromycin that primarily affect the hippocampal-entorhinal area induce amnesia of aversive maze-learning in mice for 3 days after training but are ineffective 6 or more days after training. At these later times, additional puromycin sites covering widespread forebrain areas are necessary to induce amnesia, a result that we attribute to the cerebral spread of the engram during the 6-day period. We have reported that blockade of about 60% of cerebral beta-adrenergic receptors by a single, subcutaneous injection of (-)-propranolol, a nonselective beta-receptor antagonist, inhibited engram spread for 60-90 days, at which time engram spread spontaneously occurred. In the present experiments using single doses of antagonists that appeared to block 60% of beta 2- or beta 1-adrenergic receptors, it was found that the selective beta 2 antagonist ICI 118,551 was without effect on engram spread, whereas the selective beta 1 antagonist betaxolol inhibited the spread for at least 3 months. Propranolol's effect consequently appears to be accounted for by its blockade of beta 1 receptors.

Adrenergic beta-Antagonists↗

PubMed1984

The effect of the beta-adrenergic receptor antagonist, propranolol, on the cerebral spread of a memory trace in mice.

Bi-temporal injections of puromycin that primarily affect the hippocampal-entorhinal areas consistently induce amnesia of aversive maze-learning in mice for 3 days after training but are consistently ineffective if given 6 or more days after training. At these later times, additional puromycin sites covering widespread areas of the forebrain are necessary to induce amnesia. Consistent with other evidence, these observations are interpreted to indicate that the locus of the memory trace becomes more widespread during the 6-day period. A single subcutaneous injection of (-)-propranolol (50 micrograms/kg) given either before or 2 days after training suppressed engram spread for 60-90 days, at which time engram spread spontaneously occurred. This effect of propranolol was stereospecific. Suppression of engram spread persisted for a prolonged period in spite of the rapid recovery (about 4 hr), following treatment, of the normal level of specific binding of 3H-dihydroalprenolol in membrane preparations of the cerebral hemispheres and of 125I-pindolol in selected areas of the forebrain, diencephalon and brainstem.

Animals↗

PubMed1983

Studies on memory: the cerebral spread of an engram in mice as affected by inhibitors of dopamine beta-hydroxylase.

Bitemporal injections of puromycin that primarily affect the hippocampal-entorhinal areas consistently cause amnesia of maze-learning in mice for 3 days after training but become consistently ineffective if given 6 or more days after training. At these later times, additional puromycin injection sites covering widespread areas of the forebrain are necessary to induce amnesia. These observations are interpreted to indicate that the locus of the engram has become more widespread within the 6-day period. Treatment with inhibitors of dopamine beta-hydroxylase for 3 days following training, retarded the spread of memory from a matter of days to a period of weeks. Repeated treatment with the inhibitors restricted engram spread for about 3 months; again spread was evident about a month after the last treatment. These observations imply that the mechanisms responsible for engram spread are capable of surviving for extraordinarily long periods of time.

Animals↗

PubMed1982

The cyclized C-terminal dipeptide of arginine vasopressin: metabolic stability and antagonism of puromycin-induced amnesia.

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Animals↗

PubMed1980

Studies of memory: a reevaluation in mice of the effects of inhibitors on the rate of synthesis of cerebral proteins as related to amnesia.

Tests were made of the postulates stating that the degree of inhibition of protein synthesis either (a) at training or (b) following training is the critical variable that determines the degree of amnesia. As a first step it was found that the concentrations of numerous cerebral amino acids were substantially increased in 2 strains of mice 0.5 hr after treatment with amnesic doses of the inhibitors of protein synthesis, cycloheximide (CXM) and anisomycin. This observation led, in several different experiments, to a comparison of the apparent degree of inhibition of protein synthesis derived from the acid-soluble radioactivity with that derived from the specific radioactivity of tyrosine tagged with L(1-14C)-tyrosine. In all instances the apparent degree of inhibition was decreased when based upon tyrosine's specific radioactivity. The effect of several treatments with CXM on memory of a 1-trial passive avoidance task provided data for analysis of the relationship between the degrees of amnesia and those of the more accurate estimates of inhibition of protein synthesis based upon the specific radioactivity of tyrosine. The results failed to support the views that the level of inhibition of protein synthesis at or after training are entirely sufficient to account for the behavioral rr indirect change in the brain that antagonizes the amnesic effects of the antibiotic and that consequently contributes to the survival of memory in mice trained 2 hr after a large amnesic dose of CXM.

Amino Acids↗

PubMed1980

Time-dependency of neurohypophyseal peptide attenuation of puromycin amnesia in mice.

[Ile3, Arg8]vasopressin (arginine-vasotocin), as well as the C-terminal tripeptides of the neurohypophyseal hormones arginine and lysine vasopressin, Pro-Arg-Gly-NH2 and Pro-Lys-Gly-NH2, were protective against puromycin-induced amnesia in mice when administered 24h before training. The N-protected tripeptide derivative, Z-Pro-Lys-Gly-NH2, was effective when given 5 days before training. The effectiveness of all peptides to attenuate puromycin-induced amnesia decreased as the interval between training and peptide treatment increased, indicating that the peptides influence memory processes, rather than general arousal. Z-Pro-Lys-Gly-NH2 was active at 24h after training, when the other peptides were no longer effective. Although it seems clear that neurohypophyseal hormones per se can attenuate puromycin-induced amnesia, these results are in line with the possibility that some portion of hormone action may be mediated via formation of longer-lived hormone fragments in the CNS.

Amnesia↗

PubMed1979

Distribution, survival and biological effects in mice of a behaviorally active, enzymatically stable peptide: pharmacokinetics of cyclo(Leu-Gly) and puromycin-induced amnesia.

Cyclo(Leu-Gly), the enzymatically resistant diketopiperazine formally derived from the C-terminal dipeptide sequence of oxytocin, exhibits activity in several behavioral systems. The distribution of cyclo(Leu-14C(U)Gly) in brain, and the time course of the disappearance of this labeled peptide from brain and plasma after subcutaneous injection into mice have been studied. The intact peptide was distributed equally in the five cerebral areas studied, for up to 96 hours after injection. Two exponential components were determined for peptide disappearance rates in plasma and brain; peptide half-lives in plasma up to 10 hr and from 24--96 hr after injection were, respectively, 0.8 and 33 hr; in brain, 1.0 and 42 hr. The peptide was found to accumulate in brain intracellular space to some degree. The time course of distribution of labeled cyclo(Leu-Gly) in subcellular fractions of mouse brain was also examined, and the concentration of peptide in the synaptosomal fraction was significantly correlated with the degree of protection against puromycin-induced amnesia of a maze-learning test. The results obtained not only confirm that cyclo(Leu-Gly) penetrates brain tissue intact and remains intact after peripheral administration in order to exert its behavioral effects, but, moreover, suggest an intriguing dynamic relationship between peptide concentration in the synaptosomal fraction and behavioral activity.

Amnesia↗

PubMed1979

Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice.

Pro-Leu-Gly-NH2 (MIF) and several structural analogues, all injected in 50-microgram doses daily in mice receiving morphine chronically, were found to prevent development of physical dependence as measured by changes in body temperature associated with naloxone-induced withdrawal. Dose-response studies, using again a protocol of daily injections of peptide at 50, 5, 0.5, 0.05, 0.005 microgram per mouse revealed MIF and cyclo(Leu-Gly) to be the most potent peptides and to be effective in blocking physical dependence to morphine at a dose as low as 0.5 and 0.05 microgram per mouse, respectively. The benzyloxycarbonyl derivative of MIF, Pro-Leu, and Pro- -Leu exhibited significant activities down to a dose of 5 microgram of peptide per mouse.

Animals↗

PubMed1979

Blockage of narcotic-induced dopamine receptor supersensitivity by cyclo(Leu-Gly).

We have previously reported that the administration of cyclo(Leu-Gly) to mice prior to morphinization blocked the development of tolerance to the analgesic effects of morphine as well as the development of some signs of physical dependence. In the present series of experiments, the effect of the same peptide treatment on changes in dopamine receptor sensitivity induced by chronic morphine treatment were determined. Changes in dopamine receptor sensitivity were determined by measuring (i) the effect of the dopamine agonist apomorphine on locomotor activity and (ii) the hypothermic response to another dopamine agonist, piribedil. Mice that had received the chronic morphine treatment were found to require significantly less apomorphine to produce an increase in locomotor activity, and they exhibited a significantly greater hypothermic response to piribedil than did morphine-naive mice. The injection of 0.2 mumol of cyclo(Leu-Gly) per mouse 2 hr prio to morphine treatment prevented this increased response to both dopamine agonists. Administration of the peptide after the tolerance and dependence had developed did not alter morphine tolerant and dependent states states or the enhanced response to apomorphine or piribedil. It is concluded that dopamine receptor supersensitivity may be involved in the development of narcotic tolerance and physical dependence.

Animals↗

PubMed1978

Studies on memory: spontaneous return of memory in 6-hydroxydopamine-treated mice and its relation to cycloheximide-induced transient amnesia.

We suggested previously that cycloheximide-induced transient amnesia was due in part to side-effects of the antibiotic on the central adrenergic system at the time of testing and that spontaneous return of memory depended upon recovery of the adrenergic system. To test these possibilities, mice chronically depleted of brain catecholamines (CAs) by 6=hydroxydopamine (6-OHDA) were trained in an avoidance-discrimination task and tested for spontaneous return of memory. Contrary to our hypothesis, amnesia at 24 hr after training was followed by recovery of memory by 72 hr, which indicates that recovery of memory can occur independently of adrenergic recovery. Injection of alpha-methyl-para-tyrosine immediately after training prevented return of memory at 72 hr, suggesting that the residual CAs remaining after 6-OHDA are necessary for memory to spontaneously return at this time.

Amnesia↗

PubMed1978

ADH and related peptides: effect of pre- or posttraining treatment on puromycin amnesia.

The peptide Z-Pro-Leu-Gly-NH2 attenuated puromycin-induced amnesia in mice when administered 5 days prior to training, while arginine vasopressin, lysine vasopressin and cyclo(Leu-Gly), were effective when given 24 hr before training. The activity of all peptides to inhibit puromycin-induced amnesia decreased as the interval after training and before peptide administration increased, suggesting that the peptides influence memory processes rather than generalized arousal mechanisms.

Animals↗

PubMed1978

Inhibition by Z-Pro-D-Leu of development of tolerance to and physical dependence on morphine in mice.

The peptide-Z-Pro-D-Leu, injected daily in mice receiving morphine chronically, was found to prevent development of physical dependence as measured by changes in body temperature and body weight due either to abrupt or to naloxone-induced withdrawal. On the other hand, administration of Z-Pro-D-Leu only on the last day of morphine treatment did not alter the overt signs of withdrawal. Daily administration of Z-Pro-D-Leu was also effective in blocking the development of tolerance to the analgesic and the hypothermic effects of subsequent challenge doses of morphine. However, the peptide treatment did not alter the acute effects of a challenge dose of morphine on either analgesia or body temperature. No effects on memory were noted, as evaluated in a one-trial passive avoidance task. Clinical implications of the use of Z-Pro-D-Leu are discussed.

Animals↗