Multiple central nervous system targets for eliciting beneficial effects on memory and cognition

The development of drugs for the treatment of disorders of cognition has be nefited from a more precise knowledge of the loss of specific neural pathwa ys associated with certain neurodegenerative diseases such as Alzheimer's d isease (AD). The loss of basal forebrain cholinergic neurons in AD has enge ndered the development of new compounds that target various aspects of the cholinergic system. However, limitations in the effectiveness of the most c ommon of these, the anticholinesterases, have fueled the race to provide mo re efficacious compounds. In an attempt to avoid side effects and improve e fficacy, other neuronal targets have been considered, including receptors f or norepinephrine, dopamine, serotonin, excitatory amino acids, neural pept ides, and others. Our laboratory has had the opportunity to study the memor y-enhancing potential of many of the compounds developed expressly for thes e neuronal targets in macaques. Upon reviewing 21 such studies it was evide nt that: 1) To varying degrees, pharmacological manipulation of each target yielded improved task performance. 2) Combining pharmacological targets co uld lead to additive or synergistic effects on task performance. 3) Mature adult and aged monkeys provided equivalent estimates of drug effectiveness. 4) There appeared to be no limiting level of task improvement for compound s tested in aged and younger monkeys. 5) Certain of these agents also exhib ited potential disease-modifying actions. Thus, certain memory-enhancing ag ents may prove more useful when implemented early in the course of a diseas e such as AD, and they also may enjoy a wide application for the treatment of the memory decline associated with normal aging.