In the past two decades, scientists have discovered key molecular paths that can lead to the formation of long-term memories in fruit flies, mice and rats. For example, the activation of a particular protein called CREB — which stands for "cAMP response element binding" — is required to stow memories for the long term. Building on this finding, Alan P. Kaplan and colleagues have been working to find compounds that help spur CREB into action.
The researchers screened thousands of small molecules for potential drug candidates that activate CREB and found a compound called HT-0411 that was promising. Further testing showed that HT-0411 doesn't directly activate CREB. It does so indirectly by inhibiting the enzyme monoamine oxidase B, which modulates dopamine and ultimately leads to CREB-mediated gene expression. The researchers then tweaked parts of that compound's structure and administered it to mice and rats. In memory tests, the animals that received the candidate molecule scored much higher than the control group, and they showed no signs of behavioral side effects such as changes in anxiety levels.
The authors acknowledge funding from Dart NeuroScience LLC.