Background

Amphetamine (AMP) and other psychostimulants are among the most effective psychotropic medications. Although it has been well known that there are dose- and behavior-dependent differential effects of psycho- stimulants, there is also considerable evidence that the response to these drugs varies across individuals, even to fixed doses. These variable effects have been difficult to predict a priori and to date no neurobiological explanation for them has been established. The effect of AMP and other dopamimetic agents on the PFC depends on the baseline level of PFC function, which is presumably a reflection, at least in part, of baseline dopaminergic tone (i.e., relative position on the putative inverted U). Relatively poor performers on prefrontal cognitive tasks tend to improve after stimulants, whereas high performers show no response or get worse.

The COMT val allele, presumably by compromising the postsynaptic impact of the evoked DA response, reduces prefrontal neuronal signal-to-noise ratio and makes processing less efficient.

Hypothesis

The val158- met functional polymorphism of the COMT gene would influence the effect of AMP on prefrontal cortical function: After AMP, which in the PFC increases DA levels by blocking extrasynaptic uptake at norepinephrine transporters, normal individuals homozygous for the val allele would be shifted to more optimal DA levels, thereby improving their PFC function. Also individuals homozygous for the met allele, who tend to be superior performers on prefrontal cognitive tasks and presumably have baseline synaptic DA levels closer to the peak of the theoretical inverted-U curve, would be more likely to have their DA levels shifted by AMP beyond the optimal range with a resultant decrement in PFC function.

Design & Method

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p>Double-blind, counterbalanced crossover design during two fMRI sessions. Participants were divided into three groups based on genotype (val/val, val/met, met/met). The final sample of 27 healthy volunteers (age <45, similar educational backgrounds) underwent blood oxygen level-dependent (BOLD) fMRI while performing the N-back task (PFC dependent) with increasing levels of task difficulty. Before the fMRI sessions, subjects took an executive cognition test, the Wisconsin Card Sorting Task (WCST), as prior work has shown that the COMT genotype affects performance on this task. Mood and anxiety scales were obtained after the fMRI scans on each test day.

Analysis

Main goal of this study was to explore the impact of the COMT val-met polymorphism on the effect of AMP on prefrontal cortical function. Therefore in analysis was focused on the data from the two extreme genotype groups, i.e., individuals with the high enzyme activity val/val and low enzyme activity met/met genotypes.

Result

The observations are consistent with the hypothesized inverted-U cortical-response curve to increasing DA signaling in the PFC and suggest that the likelihood of a person being on the up or down slope of the inverted U after AMP administration depends not only on the environmental demands (e.g., task conditions), but also on an individual’s COMT genotype. Indeed, val/val individuals on AMP appear in our paradigm similar to met/met individuals at baseline individuals on AMP, however, process the 3-back task more poorly than do val/val individuals at baseline. The researchers suggest that the combined effects on DA levels of AMP and high WM load push individuals with the met/met genotype beyond the critical threshold at which compensation can be made.