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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↗

PubMed1976

Biochemical actions of sympathomimetic drugs which overcome cycloheximide-induced amnesia.

Earlier investigations of sympathomimetic drugs overcoming the amnesic action of cycloheximide (CXM) in day-old chickens were extended to biochemical studies in vitro. The effects of amphetamine, norepinephrine, alpha and beta noradrenergic stimulants and receptor blockers on Na+/K+ ATP'ase activity in total homogenate of chicken forebrain were investigated. Norepinephrine and the beta stimulant, isoprenaline significantly stimulated the activity of this enzyme, while the beta blocker, propranolol inhibited activity. Amphetamine, the alpha stimulant, methoxamine and the alpha receptor blocker, piperoxane had no effect on Na/K+ ATP'ase activity in total homogenate. In a purified synaptosomal preparation, both amphetamine (5 X 10(-5) M) and norepinephrine (1 X 10(-4) M) produced a slight stimulation of Na+/K+ ATP'ase activity. A similar concentration of amphetamine (1.12 X 10(-4) M) did not inhibit 14C-leucine uptake or incorporation into protein in the synaptosomal fraction. Nor was it able to alleviate CXM inhibition of 14C-leucine incorporation into synaptosomal protein. The results are interpreted in terms of amphetamine (via release of norepinephrine) norepinephrine and isoprenaline stimulating and maintaining the labile, sodium pump-dependent, phase of memory formation for a sufficient length of time until protein synthesis inhibition by CXM wears off.

Adenosine Triphosphatases↗

PubMed1977

Comparison of the cycloheximide and food satiation effects on a discrimination task.

The effects of intraventricular cycloheximide (CHX) pretreatment were examined on the ability of rats to recall a light position discrimination task. The CHX pretreatment used inhibited brain protein synthesis at the time of training by 71%. Following treatment with CHX the animals demonstrated no retention of the task 18 hr later. Free feeding for 24 hr prior to treatment with cerebro-spinal-like fluid (CSF) produced similar effects as CHX. It is proposed that the amnesic effect of CHX in this behavioral paradigm may be a nonspecific action resulting from decreased motivation. Both the CHX-treated and satiated animals exhibited low responding levels during training, despite comparable behavioral activity levels for the CHX- and CSF-treated groups.

Animals↗

PubMed1977

Reversal of cycloheximide-induced amnesia by adrenergic receptor stimulation.

Amnesia for a multiple trial appetitive spatial dicrimination habit induced by the protein synthesis inhibitor cycloheximide (CXM) was reversed by peripheral injections of both alpha (clonidine) and beta (isoproterenol) norepinephrine receptor stimulators. Stimulation of dopamine receptors with piribedil and acetylcholine receptors with pilocarpine was ineffective in reversing amnesia. The clonidine-induced recovery was blocked by phentolamine and the isoproterenol recovery by propranolol. Examination of the temporal parameters of clonidine-induced recovery indicated that the amnesia was prevented if the agonist was injected either before training and CXM treatment, up to 1 hr after training and up to 3 hr prior to testing. Clonidine also alleviated amnesia induced by another protein synthesis inhibitor anisomycin, for a shock motivated brightness discrimination habit. These data suggest that the transient amnesia induced by CXM may be a consequence of disruption of adrenergic mechanisms and more specifically that norepinephrine may play an important role in memory retrieval.

Amnesia↗

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↗

PubMed1979

Biochemical aspects of protein synthesis inhibition by cycloheximide in one or both hemispheres of the chick brain.

Instracrnial administration of cycloheximide into one hemisphere of the chick brain resulted in inhibition of 14C-leucine incorporation into protein only in that hemisphere when the labelled amino acid was administered intracranially. With pericardial injections of labelled amino acid, inhibition of 14C-leucine incorporation was obtained in both the CXM-treated and the untreated hemisphere, when compared with bilateral saline-treated controls. The levels of inhibition were comparable to those obtained with bilateral administration of CXM. There was, however, a slight but significantly higher level of inhibition in the CXM-treated hemisphere. The results were interpreted as supporting the conclusion that monocular learning in chicks resulted in the formation of an engram only in the trained hemisphere.

Animals↗

PubMed1979

Biochemical effects of cycloheximide in developing chick brain.

The timecourses of inhibition of protein synthesis in forebrain roof 15 min to 24 hr after either intracerebral or peripheral injection of 40 microgram of cycloheximide (CXM), show maximum inhibition (68--85%) 1 hr after injection in 12 hr, 2-day- and 16-day-old chicks. In 2-day-old chicks, the level of free lysine was elevated by around 250% 1 hr after intracerebral injection of CXM. The total radioactivity in the forebrain roof/mg protein following peripheral injection of labelled lysine increased by around 80% compared to saline controls. Following unilateral injection of 20 microgram in 25 microliter CXM into a forebrain hemisphere, the inhibition of protein synthesis spread to the opposite forebrain hemisphere and both optic lobes within 5 min. Smaller volumes did not seem to give a clear unilateral inhibition capable of explaining the unilateral behavioural differences which have been reported. Central injection of CXM in 2- and 16-day-old chicks, resulted in an inhibition of liver protein synthesis of 55% and 40%, respectively. There were also gross signs of pathological effects in the liver and gall bladder. The implications of these effects of CXM are discussed in terms of the use of the drug in behavioural experiments.

Animals↗

PubMed1979

Aversive properties of cycloheximide versus memory inhibition in chickens' formation of visually cued food aversions.

No memory inhibition for a conditioned aversion in chickens, produced by pairing a novel colored food and lithium chloride (LiCl), was found when cycloheximide (CXM) was injected intracerebrally (IC) two or six hr before feeding. Good conditioned aversions were found when CXM alone was injected IC following consumption of the novel food. No aversions were found when CXM alone was injected IC two hr before feeding. Possible reasons for apparent memory inhibition using CXM in some appetitive paradigms are discussed.

Animals↗

PubMed1981

Effects of cycloheximide and puromycin on learning and retention in the cockroach, P. americana.

A new one-session T-maze training procedure for cockroaches, in which animals were trained to turn right or left to avoid shock, is described. This paradigm was utilized to investigate effects of protein synthesis inhibiting drugs on learning and retention. Cycloheximide (CXM), which inhibited protein synthesis by over 90% during the training period, did not impair acquisition and did not produce retention deficits an any interval up to 1 day after training. Puromycin (PURO), which inhibited protein synthesis by about 70% during the training period, produced amnesia 5 hr after training, while acquisition was not affected. Thus invertebrates, as well as vertebrates, are susceptible to amnesic effects of puromycin. Although PURO-injected animals showed retention deficits as measured by the number of correct turns, no retention deficit occurred for the behavioral modification consisting of an increase in runway time during the training period. Therefore, PURO appears to show specificity for the different types of longer-term memories that are formed in a training situation.

Animals↗

PubMed1982

Effects of cycloheximide, a protein synthesis inhibitor, on mouse brain catecholamine biochemistry.

Cycloheximide (CXM), a protein synthesis inhibitor, has been shown to result in a marked inhibition of central catecholamine (CA) synthetic mechanisms at doses that cause amnesia in animals. Unlike other inhibitors of CA synthesis no significant depletion of whole brain NE or DA concentrations was observed 0.75, 1, 2, 3, 4, 6, 17, or 24 hours after administration of CXM (120 mg/kg) to C57BL/6J mice. In order to investigate the underlying basis of maintenance of CA levels in face of CA synthesis inhibition, the effects of CXM on in vitro release of 3H-NE was studied in mouse hypothalamic slices. CXM, in a dose related manner, significantly inhibited the potassium stimulated release of NE from hypothalamic slices. Anisomycin, another protein synthesis inhibitor, similarly inhibited NE release. These studies further document the effects of protein synthesis inhibitors on CA mechanisms and suggest that disruption of CA biochemistry may play a role in the amnesia observed after administration of protein synthesis inhibitors.

Animals↗

PubMed1983

Amnesia attenuation specificity: propranolol reverses norepinephrine but not cycloheximide-induced amnesia.

Post-trial injections of norepinephrine (NE) or cycloheximide (CHX) into the amygdala produces a long-term retention deficity (amnesia) for a 1-trial footshock experience in rats. concomitant post-trial injections of the adrenergic antagonist, propranolol, prevents NE-, but not CHX-induced amnesia. These results indicate separate mechanisms of action for amnesia produced by intracranial CHX and NE injections.

Amnesia↗

PubMed1984

Investigation of the reported protective effect of cycloheximide on memory.

Many findings support the hypothesis that formation of long-term memory requires synthesis of proteins in the nervous system close to the time of learning. This hypothesis has been challenged recently by reports that the protein synthesis inhibitor cycloheximide (CYC) injected 2 hr prior to passive avoidance training in mice or rats attenuated the memory impairment induced by a usually amnestic dose of CYC administered 30 min pretraining. To investigate the reports of a "protective" effect of the prior injection, we attempted to replicate them and test their generality. For replication we administered either paired injections of CYC--120 mg/kg 2 hr prior to training and 30 mg/kg 30 min prior to training--or single injections of CYC (either 120 mg/kg or 30 mg/kg) 30 min pretraining and tested for retention of the passive avoidance habit either 1 or 7 days later. No attenuation of amnesia was observed at 1 day tests. Attenuation of amnesia following the double injection of CYC was observed at 7 day tests. When another protein synthesis inhibitor, anisomycin, was used in the same experimental design, there was no "protective" effect; two injections of anisomycin produced greater memory impairment for the passive avoidance habit than did the single low dose. Also, for active avoidance training, two successive injections of CYC caused significantly greater amnesia than did a single dose; this is the opposite of a "protective" effect. We suggest that the reported "protective" effect of CYC on memory is an as yet unexplained phenomenon that does not generalize to other antibiotic drugs and is specific to the passive avoidance task.

Animals↗

PubMed1986

The antagonistic effects of naloxone on cycloheximide and anisomycin-induced amnesia.

The amnesia induced by cycloheximide (CXM) injected SC and by CXM or anisomycin injected ICV immediately after the training test was antagonized in combination with an opiate antagonist, naloxone (NLX). This antagonism occurred on both the passive avoidance- and escape-learning responses in a dose-dependent manner in mice. NLX alone (0.3-10.0 mg/kg) did not alter the performances of these tasks. Furthermore, the decrease in retention performance on shuttle avoidance in rats induced by CXM was also antagonized by NLX. Treatment with CXM and/or NLX did not affect spontaneous locomotor activity. The interaction of these drugs on the performance of the passive avoidance- and escape-learning and the shuttle avoidance tasks may be related to neurochemical memory processes. These results suggest that an opioid system may participate in the amnesic actions induced by protein synthesis inhibitors in these models.

Amnesia↗

PubMed1988

Role of cholinergic and GABAergic neuronal systems in cycloheximide-induced amnesia in mice.

The role of cholinergic and GABAergic neuronal systems on the cycloheximide (CXM)-induced amnesia was investigated using the step-down-type passive avoidance task in mice. CXM (7.5-120 mg/kg, SC) given just after the training caused amnesia (indicated by short latency to step down from the platform on the grid floor) in the retention test conducted 24 hr later in a dose-dependent fashion. In the CXM (60 mg/kg)-treated mice, a choline esterase inhibitor, physostigmine (PHY; 0.125 and 0.25 mg/kg, IP), or GABA agonists, muscimol (1 and 2 mg/kg, IP) and baclofen (6 and 12 mg/kg, IP), given just after training markedly prolonged step down latency (SDL), indicating reversal of amnesia. The antiamnesic action of PHY (0.125 mg/kg) was almost completely antagonized by a central acetylcholine antagonist, scopolamine (3 mg/kg, SC), but not by a peripheral acetylcholine antagonist, butylscopolamine (3 mg/kg, SC). Furthermore, the antiamnesic action of muscimol (2 mg/kg) was reversed by GABA antagonists, picrotoxin (0.5 mg/kg, SC) and bicuculline (0.5 mg/kg, SC), while the effect of baclofen (12 mg/kg) was reversed by picrotoxin (0.5 mg/kg), but not by bicuculline (0.5 mg/kg). These results suggest that the dysfunction of cholinergic and GABAergic neuronal systems play an important role in the CXM-induced memory impairment on the passive avoidance task.

Amnesia↗

PubMed1989

Effects of 5-HT2 receptor antagonist on cycloheximide-induced amnesia in mice.

A role played by serotonergic neuronal system in cycloheximide (CXM)-induced amnesia was studied in mice using a step-down passive avoidance task. CXM (30 mg/kg SC) given immediately after training caused impairment of memory. Nonselective serotonin (5-HT) antagonist methysergide and selective 5-HT2 antagonist ritanserin significantly attenuated impairment of memory caused by CXM. 5-HT1 antagonist (+/-)-pindolol had no effect on CXM-induced amnesia. The antiamnesic effect of ritanserin on CXM-induced amnesia was antagonized by 5-HT (ICV), but not by nonselective 5-HT agonist 5-methoxy-N,N-dimethyltryptamine and 5-HT1A selective agonist 8-hydroxy-2-(di-n-propylamino)tetralin at the dose level which did not cause the memory disruption. Scopolamine antagonized the antiamnesic effects of methysergide and ritanserin on CXM-induced amnesia. These results suggest that 5-HT2 receptors and cholinergic neuronal system may play an important role in memory formation.

Amnesia↗

PubMed1995

Cycloheximide inhibits context memory and long-term habituation in the crab Chasmagnathus.

A shadow moving over head elicits an escape response in the crab Chasmagnathus that habituates promptly and for a long period. The effect of the protein synthesis inhibitor cycloheximide (CY) on this long-term memory was analyzed. Two hours after injection, 10 micrograms CY inhibited [14C]-amino amino acid incorporation into cerebral plus thoracic ganglia by 88% and 20 micrograms by 92%, but no inhibition was found at 24 h. A single injection of 10-20 micrograms CY given 30 min before training, failed to affect the short-term habituation. Similar doses impaired both context memory (CM) and long-term habituation (LTH) when tested at 72 and 120 h but only CM at 24 h. Such a disparity was explained by an unspecific depressing effect upon the response, attributed to an interaction between CY and training. The hypothesis was confirmed, because CY injected immediately after training disclosed amnestic effect at 24 h on both CM and LTH. A similar effect was proven when animals were injected at 2 h but not at 6 h after training. Results from experiments with pretraining and pretesting injections put aside a state-dependence or retrieval deficit effects of the drug. Taken together, findings of this article argue strongly for de novo protein synthesis as a mechanism of LTH and for the close relation between CM and LTH.

Amino Acids↗

PubMed1975

Effects of cycloheximide on virus RNA replication in an inducible line of polyoma-transformed rat cells.

In this article, we describe two distinct effects of cycloheximide (CH), a potent inhibitior of protein synthesis, on the replication of polyoma virus (PV) DNA in an inducible line of PV-transformed rat cells (LPT cells). Exposure of LPT cells to CH causes up to an 8 fold increase in the cellular concentration of PV DNA determined by molecular hybridization. The same treatment inhibits cell division and chromosomal DNA replication. However, the amount of chromosomal DNA per cell is not affected by the drug. In LPT cells treated with mitomycin C (MMC), PV DNA replication is enhanced after 7 hr. During the period extending from 7 hr to 24 hr, the concentration of virus DNA increases at least 100 fold. CH added to the cells 0-7 hr after treatment with MMC inhibits the replication of PV DNA by 90-100%. The inhibition is less effective in cells exposed to CH from 7 hr and on. The inhibitory effect is reversible: virus DNA synthesis is resumed after removal of CH from the growth medium. Thus CH acts as an inducer of virus DNA synthesis in cells whose resident viral genome is repressed, but inhibits the autonomous replication of the activated genome following induction with MMC.

Animals↗

PubMed1975

Effects of cycloheximide on the "autocatalytic" nature of the maturation promoting factor (MPF) in oocytes of Xenopus laevis.

It is shown that a factor arising during the course of maturation in amphibian oocytes is by itself capable of inducing maturation when injected into recipient oocytes even after a series of 10 transfers. The mechanism of action of this phenomenon is shown to be under translational control. Experiments using cycloheximide suggest that MPF does not need protein synthesis for germinal vesicle breakdown (GVBD), but does require a translational step when serially transferred in order to sustain its renewal ("autocatalytic") capacity. It is further shown that oocytes of Xenopus laevis lend themselves to an in vitro system, since when matured under the action of some steroids (progesterone or hydrocortisone), they are capable of supporting functional maturation with cleavage and development after having received a transplanted blastula nucleus.

Animals↗