Acetoxycycloheximide

Abstract: We have reported1-3 that) mice trainied while their cerebral protein synithesis was markedly inhibited by acetoxycycloheximide learned normally and remembered normally for more than three hours after training but had markedly impaired "long-term" memory.4 These studies suggest that learning and "shortterm" memory are inot dependent on cerebral protein synthesis, but that it is necessary for the establishrnent of "long-term" memory. Acetoxycycloheximide was found to be maximally effective in impairing the formation of "long-term" memory if it was given prior to training so that inhibition of cerebral protein synthesis was established during training.1-3 The drug was slightly effective if given immediately after training3 and completely ineffective if given 30 minutes later. This suggests that the cerebral protein synthesis apparently required for "long-term" memory normally occurs during training or within minutes after training, or both. In the previous experiments, it was not possible to determine whether "shortterm" memory could lead to the formation of "long-term" memory at times later than a few minutes after training. Although "short-term" memory persisted for hours after training, inhibition of cerebral protein synthesis by acetoxycycloheximide also persisted for this period of time. Therefore, "conversion" of "short-term" memory to "long-term" memory hours after training would presumably be blocked by the persistent action of the inhibitor of cerebral protein synthesis. Recently, we have found that cycloheximide inhibits cerebral protein synthesis as intensely but more transiently than acetoxycycloheximide, and shares with it the ability to prevent the formation of "long-term" memory.5 In the present experiments, the doses of cycloheximide that were used inhibited approximately 95 per cent of cerebral protein synthesis during training but permitted very marked recovery within three hours after training. Despite the extensive recovery of the capacity of the brain to synthesize protein at a time when "short-term" memory still remained, "long-term" memory was not spontaneously established. However, the introduction of manipulations that generate "arousal" led to the development of "long-term" memory if introduced at a time when "short-term" memory persisted (i.e., 3 hr after traininig). The reestablishment of marked inhibition of cerebral protein synthesis prior to the onset of the "arousal"-producing manipulation blocked the establishment of "longterm" memory. Materials and ill ethods.Male ,Swiss albinto iice weighing approximately 30 gm were obtained from the Charles River Breeding Corp. They were trained to escape shock by choosing the lighted limb of a T-maze to a criterion of five out of six consecutive correct responses as described previously.2 In other experiments, they were trained to choose the left limb of a T-maze for water reinforcement to a criterion of three out of four consecutive