Pharmacogenetic tools for the development of target-oriented cognitive-enhancing drugs

The identification of the anatomical and physiological substrates involved in the regulation of the dorsolateral prefrontal cortex function in humans provided the basis for the understanding of mechanisms involved in cognitive and executive function under normal as well as pathological conditions. In this context, substantial evidence indicates that alterations in monaminergic function in the dorsolateral prefrontal cortex significantly contributes to the cognitive impairments present in schizophrenia, attention deficit disorders, and other neuropsychiatric conditions. The development of a number of compounds that selectively increase extracellular dopamine (DA) concentrations in the dorsolateral prefrontal cortex but not in subcortical areas by either blocking its metabolism or reuptake, or increasing its release, or that directly activate postsynaptic DA-1 receptor mechanisms provided powerful pharmacotherapeutic tools to mitigate the cognitive deficits brought about by the dopaminergic alterations of the prefrontal cortex. More recently, the findings that polymorphisms of the catecholamine-O-methyl-transferase gene may also modify the effect of these drugs on the prefrontal cortex points toward a more specific genotype-based neuropsychopharmacology for the treatment of cognitive deficits in schizophrenia as well as in a number of other neuropsychiatric conditions. The ability of these compounds to increase DA load selectively in the frontal cortex and not on subcortical systems allows a targeted intervention without the stimulant-like effects observed with older drugs used to treat those conditions. © The American Society for Experimental NeuroTherapeutics, Inc.