Few areas of neurobehavioral research seemed more promising in the early sixties than that investigating the relationship between protein synthesis and learning. The conceptual framework for this research was derived directly from molecular biology, which had shown that genetic information is stored in nucleic acids and expressed in proteins. Why not acquired information as well?
The first step toward establishing a connection between protein synthesis and learning seemed to be to block memory (cause amnesia) by interrupting the production of proteins. We were fortunate in finding a nonlethal dosage of puromycin that could, it first appeared, thoroughly inhibit brain protein synthesis as well as reliably produce amnesia.
Before the actual connection between protein synthesis and learning could be established, however, we began to have doubts about whether inhibition of protein synthesis was in fact the method by which puromycin produced amnesia. First other drugs, glutarimides—themselves potent protein-synthesis inhibitors—either failed to cause amnesia in some situations where it could easily be induced by puromycin or produced an amnesia with a different time course from that of puromycin. Second puromycin was found to inhibit protein synthesis by breaking certain amino-acid chains, and the resulting fragments were suspected of being the actual cause of amnesia in some cases. Third, puromycin was reported to cause abnormalities in the brain including seizures. Thus, not only were decreased protein synthesis and amnesia dissociated, but alternative mechanisms for the amnestic action of puromycin were readily suggested
So, puromycin turned out of be a disappointment. It came to be regarded as a poor agent for amnesia studies, although, of course, it was poor only in the context of our original paradigm of protein-synthesis inhibition. In our frustration, our initial response was simply to change drugs rather than cur conceptual orientation. After many such disappointments, however, it now appears unlikely that we will make a firm connection between protein synthesis and learning merely by pursuing the approaches of the past. Our experience with drugs has shown that all the amnestic agents often interfere with memory in ways that seem unrelated to their inhibition of protein synthesis, More importantly, the notion that the interruption or intensification of protein production in the brain can be related in cause-and-effect fashion to learning now seems simplistic and unproductive. Remove the battery from a car and the car will not go. Drive the car a long distance at high speed and the battery will become more highly charged. Neither of these facts proves that the battery powers the car only a knowledge of the overall automotive system will reveal its mechanism of locomotion and the role of the battery within that system.