UC Irvine

Positive allosteric modulators of α-amino-3-hydroxyl-5-methyl-4-isoxazole- propionate (AMPA)–type glutamate receptors (“ampakines” and functionally related compounds) constitute a relatively new class of psychoactive drugs that enhance fast, excitatory transmission in the brain. Because of this effect, ampakines reduce the threshold for inducing memoryrelated changes to synapses and improve learning in animals across species and paradigms. While most CNS drugs target neurons that project in a onestep, parallel fashion to a multitude of sites, ampakine-type agents act on the multiple connections found in serial brain networks. This results in a multiplier effect for the drug, likely to be most pronounced in the elaborate circuits found in the cortex, thereby intensifying cortical regulation of lower brain areas (“pharmacological encephalization”). Evidence that the compounds are effective in animal models of psychiatric disorders associated with abnormal brainstem activity is in agreement with this hypothesis. The possibility that expanding cortical networks will lead to cognitive, as opposed to memory, enhancement in normal brains is largely unexplored. Finally, positive modulators increase the production of brain growth factors that promote plasticity and neuronal viability; upregulation is associated with neuroprotection, growth, and improved functional outcomes in different disease models.