Tolcapone Improves Cognition and Cortical Information Processing in Normal Human Subjects

Abstract

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 tolcaponeinduced 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.

Dopamine, Corticostriatal Connectivity, and Intertemporal Choice

“…Consistent with this hypothesis, a behavioral study of prepulse inhibition demonstrated that subjects with a more active form of the COMT enzyme (and thus lower cortical dopamine tone) showed improved performance on tolcapone, but those with a less active form did not (Giakoumaki et al, 2008). Similarly, in a study of executive function, Apud et al (2007) found that subjects with a more active form of COMT showed greater improvements on tests of set shifting and verbal episodic memory when administered tolcapone. These results are in keeping with our finding that subjects with higher baseline impulsivity may benefit the most from tolcapone.…”

Orientation and Cellular Distribution of Membrane-bound Catechol-O-methyltransferase in Cortical Neurons

“…Thus, inhibition of COMT might be expected to improve dopamine mediated cortical cognition without causing addiction related behaviors linked to increased dopamine in the ventral striatum. Indeed, clinical studies with tocalpone suggest improvement of cortical function without striatal effects (29).…”

Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics

“…To address this, we recently examined whether tolcapone would improve working memory/executive function in normal control subjects. 55 Specifically, we predicted that increased prefrontal efficiency associated with tolcapone would be most pronounced in val homozygotes, with likely a worsening in met homozygotes, in line with the proposed inverted U function of prefrontal dopamine signaling. 46 In a double-blind, placebo-controlled crossover study, 47 healthy controls (including 15 val homozygotes and 11 met homozygotes) were administered 200 mg of tolcapone or placebo three times a day for 7 days.…”

“…46 In a double-blind, placebo-controlled crossover study, 47 healthy controls (including 15 val homozygotes and 11 met homozygotes) were administered 200 mg of tolcapone or placebo three times a day for 7 days. 55 Each subject completed a battery of tests sensitive to prefrontal cognitive function, at the conclusion of each arm of the protocol. In the main, results obtained supported our hypotheses.…”