José A Apud | PubMed Health

PubMed2006

Tolcapone improves cognition and cortical information processing in normal human subjects.

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction. To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcapone-induced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.

Adult↗

PubMed2006

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.

Benzhydryl Compounds↗