Hasker P. Davis

Cerebral protein synthesis inhibition and discrimination training: effects of extent and duration of inhibition

Anisomycin, an inhibitor of cerebral protein synthesis, impaired memory in mice measured 5, 7, or 14 days after discrimination training. A large dose of anisomycin (210 mg/kg) impaired memory to a greater extent than a smaller dose (30 mg/kg) and inhibited cerebral protein synthesis more completely. The impairment produced by the smaller dose was not increased by maintaining protein synthesis inhibition for at least 13 1/2 hr beyond training with repeated injections (30 mg/kg). Moreover, memory was not measurably impaired by a prolonged period of inhibition, beginning 1-1/2 hr after training. The amnesic effects of the large dose could not easily be explained by illness or by state-dependent effects. The results suggest that, in the case of discrimination training, the amnesic effects of cerebral protein synthesis inhibition are determined largely by the extent of inhibition at the time of training, rather than by the duration of inhibition. For discrimination habits, sufficient protein synthesis for the establishment of long-term memory appears to occur close to the time of training.

Recovery as a function of the degree of amnesia due to protein synthesis inhibition

Retrograde amnesia following inhibition of cerebral protein synthesis has generally been explained as either a failure of consolidation or impairment of a retrieval mechanism. Major evidence for the retrieval hypothesis is provided by studies which utilize a reminder (usually footshock) to attenuate the effect of the protein inhibitor. To examine this question, mice were injected subcutaneously with anisomycin (1 mg/animal, 7 mg/animal, or 1 mg/animal every 2 hr x 7) and given one training trial in a passive avoidance box. All animals received a single retention test on each of four consecutive days, starting either 1, 7, or 21 days after training. One-half of the mice in each group received a footshock reminder 1 hr after their initial test. The footshock reminder did not attenuate the inhibitor-induced amnesia, but multiple testing did produce partial recovery in animals demonstrating some memory of training (both Saline and Anisomycin animals). Animals injected with anisomycin whose testing began 1 day after training demonstrated partial recovery irrespective of drug dosage level. The extent of amnesia and recovery were dependent upon both drug dosage and training-test interval. Implications for the consolidation and retrieval hypotheses are discussed.

Inhibitors of cerebral protein synthesis: Dissociation of aversive and amnesic effects

It has been reported that cycloheximide, a protein synthesis inhibitor, produces conditioned aversion. This finding raised the possibility that the amnesic effect of this drug could be due to its aversive effects rather than to inhibition of cerebral protein synthesis required for the formation of long-term memory. The present study indicates that (1) amnesic doses of cycloheximide and anisomycin, two protein synthesis inhibitors, produced conditioned gustatory aversion; (2) lithium chloride produced as much conditioned aversion as an amnesic dose of anisomycin and more aversion than cycloheximide, but did not affect memory. Therefore the aversive effect of protein synthesis inhibitors, as measured by the conditioned gustatory aversion test, is not sufficient to explain their amnesic effect.

Inhibition of cerebral protein synthesis: performance at different times after passive avoidance training ☆

Inhibition of cerebral protein synthesis impairs long-term memory in a variety of species and tasks. Recently it was reported that subcutaneous injection of the protein synthesis inhibitor cycloheximide impaired short-term retention, measured 10 min after training in a passive avoidance task. To examine the possibility that inhibition of cerebral protein synthesis may sometimes disrupt short-term memory, mice were injected subcutaneously with cycloheximide (120 mg/kg) or anisomycin (150 mg/kg), or bitemporally with cycloheximide or anisomycin (100 mug/side) and given one training trial in a passive avoidance box. Subcutaneously injected cycloheximide reduced step-through latencies 10 min after training as reported previously, but anisomycin or bitemporally injected cycloheximide did not. All 4 drug groups exhibited impaired long-term memory. Since the results obtained at short intervals after training varied depending on the drug and route of injection, the impairment produced by subcutaneous cycloheximide at 10 min after training cannot be attributed to inhibition of cerebral protein synthesis. It is suggested that performance at short intervals after training reflects drug side effects on step-through behavior. By contrast, the impairment obtained at long intervals after training is consistent with the hypothesis that cerebral protein synthesis is required for formation of long-term memory.

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

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.

Effects of anisomycin on retention of the passive-avoidance habit as a function of age

Three age groups of male Swiss albino CD-1 mice (2-3 mo, 6-7 mo, and 14-15 mo) were treated with a 120 mg/kg dose of the protein synthesis inhibitor anisomycin or with an equal volume of saline at various times before and after training (20 min pretraining, 0, 10, 30, or 180 min posttraining) in a shock motivated passive-avoidance task. Young (2-3 mo) and intermediate-aged (6-7 mo) mice treated with anisomycin before or immediately after training demonstrated impaired retention at a 7 day test, but retention was normal for mice injected 10, 30 or 180 min posttraining. The older mice (14-15 mo) showed similar results, with one exception: those older mice injected with anisomycin 10 min posttraining were significantly impaired in retention as compared to older saline controls and to identically treated young or intermediate-age mice. The prolonged gradient of retrograde amnesia demonstrated by older mice could not be accounted for by impaired acquisition, impaired short-term memory, altered spontaneous locomotor activity, or differential inhibition of brain protein synthesis.

The effect of age on the learning of a nondeclarative category classification task

A category classification task was administered to participants in their twenties through their eighties. Participants studied a set of high distortions of a prototype dot pattern and were then asked to choose whether or not a new set of dot patterns (random patterns, high distortions, low distortions, and the prototype) belonged to the same category of dot patterns as studied. Participants were also administered a recognition test after studying a second set of dot patterns. There were no significant differences for age groups on the pattern recognition test. In 2 of the 3 analyses of the category classification task, there were no significant age effects. However, there was a small age effect in one analysis with the young making more accurate classifications on two aspects of the task. The results are consistent with the view that small age-related effects may exist for some tests of nondeclarative memory.