Inhibition of cerebral protein synthesis: Dissociation of nonspecific effects and amnesic effects

doi:10.1016/S0163-1047(80)93202-1

Behavioral and Neural Biology

Volume 28, Issue 1, January 1980, Pages 99-104

https://doi.org/10.1016/S0163-1047(80)93202-1 Get rights and content

Injection of 210 mg/kg of anisomycin 5 hr prior to training produced more nonspecific behavioral side effects at the time of training than did a low dosage (30 mg/kg) given 20 min prior to training. Yet the low dosage 20 min pretraining produced greater protein synthesis inhibition at training and greater impairment of retention of passive avoidance training than did the high dosage 5 hr pretraining. These results demonstrate that the level of protein synthesis inhibition at or near the time of training is the critical factor for inducing amnesia, and not nonspecific side effects of a protein synthesis-inhibiting drug. Various alternative hypotheses would also predict greater amnesia after the high dosage of anisomycin given 5 hr prior to training than after the amnestic low dose given 20 min prior to training. Thus, these results provide further support for the hypothesis that brain protein synthesis is required for long-term memory formation.

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Recognising the adverse effect of electroconvulsive shock, pharmacological approaches were then later used. For example, protein synthesis inhibition (Davis et al., 1976, 1980) was often used to induce amnesia. By applying protein synthesis inhibition in the amygdala after fear memory reactivation, Nader et al. (2000) show an impairment in post-reactivation long-term memory (Fig. 1A).
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Reconsolidation: Historical Perspective and Theoretical Aspects
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A retrieved memory in its active state becomes labile and is susceptible to disruption by an amnestic agent. This phenomenon, first described as cue-dependent amnesia nearly 50 years ago, has received renewed interest in the 21st century because of obvious clinical implications. The construct of reconsolidation has emerged to define hypothetical processes necessary to stabilize memory after its reactivation. This had led to a debate reminiscent of the intense controversy surrounding the initial consolidation literature in the 1960s. A new view of memory is encouraged by functional imaging studies confirming the theoretical position that all new memories are integrated into an existing functional network, making retrieval an integral part of the memory process. This analysis does not allow a clear demarcation between consolidation and retrieval, and in this view, it can be assumed that every retrieval operation should trigger a reconsolidation process.
This chapter does not attempt to provide a full and comprehensive review of the burgeoning literature addressing the molecular and cellular underpinnings of reconsolidation, but, instead, focuses on the historical background and theoretical controversies from which the concept emerged and the evolving view of memory as a dynamic and adaptive property of the nervous system.
Reconsolidation: Historical perspective and theoretical aspects
2007, Learning and Memory: A Comprehensive Reference
A retrieved memory in its active state becomes labile and is susceptible to disruption by an amnestic agent. This phenomenon, first described as cue-dependent amnesia more than 40 years ago, has received renewed interest in the twenty-first century, because of obvious clinical implications. The construct of reconsolidation has emerged to define hypothetical processes necessary to stabilize memory after its reactivation. This had led to a debate reminiscent of the intense controversy surrounding the initial consolidation literature in the 1960s. A new view of memory is encouraged by functional imaging studies confirming the theoretical position that all new memories are integrated into an existing functional network, making retrieval an integral part of the memory process. This analysis does not allow a clear demarcation between consolidation and retrieval, and in this view, it can be assumed that every retrieval operation should trigger a reconsolidation process.
Protein synthesis and the mechanisms of lasting change in anxiety induced by severe stress
2006, Behavioural Brain Research
Brief, unprotected exposure of rats to cats (predator stress) may be lastingly anxiogenic in a variety of tests of rodent anxiety. Recent findings suggest that predator stress induced plasticity in neural circuitry implicated in fear learning underlies some of these anxiogenic effects. In addition, recent work implicates a consolidation-like process in the impact of predator stress on anxiety in that effects of predator stress may be interrupted by immediate post stressor pharmacological interventions. The present study tested whether “consolidation” of the anxiogenic effects of predator stress were dependent on protein synthesis. In addition, the study examined whether a protein synthesis dependent reconsolidation-like process was at work when rats were exposed to a cat twice. Anisomycin (210 mg/kg) or vehicle (Tween 80 in saline) was injected subcutaneously 1 min after a single cat exposure (consolidation test paradigm) or a 1 min after a second cat exposure (reconsolidation test paradigm) and behavior tested 7–8 days after predator stress. In the consolidation test paradigm, anisomycin blocked the anxiogenic effects of predator stress in the elevated plus maze (EPM) measured with open arm exploration. Moreover, anisomycin blocked the potentiation of startle by predator stress when rats were startled in the light, but not when startled in the dark. In contrast, the delay of habituation of startle produced by predator stress was unaffected by anisomycin. Suppression of risk assessment in the EPM by predator stress was not affected by anisomycin either. In startle testing, vehicle injection 1 min after predator stress led to a lasting suppression, rather than enhancement of startle response. Vehicle plus predator stress enhanced and prolonged corticosterone level changes sampled over 30–180 min after treatment when compared to handled or predator stressed only rats. In addition, predator stress plus vehicle suppression of startle was blocked by a benzodiazepine anxiolytic (chloradiazepoxide) or the glucorticoid receptor (GR) blocker RU486. Both drugs returned startle to the predator stressed only heightened levels. It is argued that an added anxiogenic effect of vehicle injection plus predator stress leads to a suppression, rather than enhancement of startle. Startle suppression appears to be mediated, in part, by activation of GR by corticosterone which engages a protein synthesis dependent process, since anisomycin blocked the startle suppressive effects of vehicle. Startle suppression also appeared to be independent of the startle enhancing effect of predator stress and in competition with it. Since predator stress may model aspects of hyperarousal associated with post traumatic stress disorder (PTSD), implications of these findings for understanding of mechanisms of initiation of the disorder and for treatment are discussed.
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2002, Neuron
Learning of new information is transformed into long-lasting memory through a process known as consolidation, which requires protein synthesis. Classical theory held that once consolidated, memory was insensitive to disruption. However, old memories that are insensitive to protein synthesis inhibitors can become vulnerable if they are recalled (reactivated). These findings led to a new hypothesis that when an old memory is reactivated, it again becomes labile and, similar to a newly formed memory, requires a process of reconsolidation in order to be maintained. Here, we show that the requirement for protein synthesis of a reactivated memory is evident only when the memory is recent. In fact, memory vulnerability decreases as the time between the original training and the recall increases.
Protein synthesis inhibitor cycloheximide dose-dependently decreases formalin-induced c-Fos protein and behavioral hyperalgesia in rats
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We had previously demonstrated that c-fos antisense oligodeoxynucleotides dose-dependently suppressed formalin-induced c-Fos protein and behavioral hyperalgesia. To test whether de novo protein synthesis is required for the development of persistent pain after peripheral inflammation, we observed formalin-induced spinal c-Fos protein and nociceptive behaviors following pretreatment with cycloheximide, a protein synthesis inhibitor. Cycloheximide dose-dependently inhibited formalin-induced spinal c-Fos protein and tonic nociceptive responses. The possible non-specific effects other than protein synthesis inhibition on nociceptive behavior were carefully discussed and excluded. These results provide further support to the hypothesis that de novo protein synthesis is essential for the development of behavioral hyperalgesia.

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¹: This research was supported by ADAMHA Grant R01MH26704 and the Division of Biomedical and Environmental Research of the U.S. Department of Energy, Contract W-7405-ENG-48. L.R.S. was supported by the Medical Research Service of the Veterans Administration and by a grant from the Spencer Foundation. We thank Ann E. Orme for biochemical assistance.

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Brief reportInhibition of cerebral protein synthesis: Dissociation of nonspecific effects and amnesic effects

Pharmacology Biochemistry and Behavior

Brain Research

Brain Research

Behavioral Biology

Brain Research

Brief report
Inhibition of cerebral protein synthesis: Dissociation of nonspecific effects and amnesic effects