Tuesday, December 16, 2008

Working memory and COMT inhibitors - the nicotine example

Obviously, I'm not considering smoking as an aide to my son's limited short term memory. It is interesting, however, to note how substances associated with smoking act on the brain ...

FuturePundit: Gene Variant Makes Nicotine Withdrawal Harder


Spurred by their previous findings that carriers of the catechol-O-methyltransferase (COMT) val gene variant are more susceptible to smoking relapse, the Penn researchers set out to learn if smokers with this genetic background would be more likely to exhibit altered brain function and cognitive deficits during periods of abstinence from smoking.

...Results showed that smokers with the COMT val/val genotype suffered greater deficits in working memory and brain function when they had refrained from smoking for 14 or more hours, compared to their performance on this task when they had been smoking as usual....

... Inhibitors of this COMT enzyme might work to ease withdrawal from nicotine. Inhibitors of COMT already are known to increase working memory...

One method may be to offer carriers of this gene targeted therapies with drugs like COMT inhibitors, some of which have been shown to increase working memory in healthy volunteers.

The researchers were trying to understand why some people have a much harder time stopping smoking that others. It seems at least some of these persistent smokers experience brain dysfunction when they stop. The article does not tell us whether these people are experiencing a return to baseline cognition or whether they're experiencing a transient impairment. I assume the latter.

Even as smoking has become mercifully unusual in wealthier parts of North America, there's been more interest in the pharmacologic action of chemicals produced by the nicotine plant.

This related ticle on COMT inhibitors and executive function is interesting. Tolcapone is used to treat Parkinson's Disease (emphases mine):

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.

Please note that some people got worse on Tolcapone. I think we're a long way (20 years) from a safe medicine that can improve working memory, but this will be an interesting thread to follow.

No comments: