COMT Val158Met genotype selectively alters prefrontal [18F]fallypride displacement and subjective feelings of stress in response to a psychosocial stress challenge

Abstract

Catechol-O-methyltransferase (COMT) plays an essential role in degradation of extracellular dopamine in prefrontal regions of the brain. Although a polymorphism in this gene, COMT Val(158)Met, affects human behavior in response to stress little is known about its effect on dopaminergic activity associated with the human stress response, which may be of interest for stress-related psychiatric disorders such as psychosis. We aimed to investigate the effect of variations in COMT genotype on in vivo measures of stress-induced prefrontal cortex (PFC) dopaminergic processing and subjective stress responses. A combined sample of healthy controls and healthy first-degree relatives of psychosis patients (n = 26) were subjected to an [(18)F]fallypride Positron Emission Tomography scan. Psychosocial stress during the scan was induced using the Montreal Imaging Stress Task and subjective stress was assessed every 12 minutes. Parametric t-maps, generated using the linear extension of the simplified reference region model, revealed an effect of COMT genotype on the spatial extent of [(18)F]fallypride displacement. Detected effects of exposure to psychosocial stress were unilateral and remained restricted to the left superior and right inferior frontal gyrus, with Met-hetero- and homozygotes showing less [(18)F]fallypride displacement than Val-homozygotes. Additionally, Met-hetero- and homozygotes experienced larger subjective stress responses than Val-homozygotes. The direction of the effects remained the same when the data was analyzed separately for controls and first-degree relatives. The human stress response may be mediated in part by COMT-dependent dopaminergic PFC activity, providing speculation for the neurobiology underlying COMT-dependent differences in human behaviour following stress. Implications of these results for stress-related psychopathology and models of dopaminergic functioning are discussed.

Figure 1. Graphical overview of the scanning protocol.

Prior to [¹⁸F]fallypride injection into the antecubital vein at t = 0, a CT scan was obtained. After injection a 70-minute control block was followed by a 5-minute break. Then, a second CT scan was obtained, followed by a brief block of rest. The stress condition started at t = 80 and scanning ended at approximately t = 160, followed by a third and final CT scan.

Figure 2. Genotype-dependent [¹⁸F]fallypride displacement in response to psychosocial stress.

Comparison of the spatial extent to which [¹⁸F]fallypride displacement could be observed in VOIs, using parametric maps. Val-homozygotes showed the greatest difference in % of voxels active in response to stress per VOI (reflecting increased [¹⁸F]fallypride displacement), followed by Met-hetero- and homozygotes. The % of voxels active per VOI was not significantly different for Met-hetero- and homozygotes. Depicted numbers represent % of voxels active associated with stress (condition). Val/Met and Met/Met genotype are depicted separately to visualize the direction of the effect, but were grouped for the analyses. * = Exceeding threshold of p(corrected)<.05; n.s. = not significant. Note that the depicted % indicate the spatial extent to which ligand displacement was detected yet the % do not indicate VOI activity as a whole.

Figure 3. Mean t-maps per genotype group (Val/Val, Val/Met, Met/Met) reflecting [¹⁸F]fallypride displacement in response to psychosocial stress.

Mean t-maps per genotype group (Val/Val, Val/Met, Met/Met) in transversal (left), sagittal (middle) and coronal (right) sections showing the spatial extent of [¹⁸F]fallypride displacement throughout the right inferior frontal gyrus (rlFG, BA 44) in response to the psychological stress task. Individual maps of t (with a cutoff of t>4.5, reflecting a one-sided t-test investigating increased ligand displacement versus the control state) were averaged for Val/Val (top row), Val/Met (middle row and Met/Met (bottom row) and illustrate the spatial extent of task-induced ligand displacement. Individual t-maps were generated using γ (t = γ/sd(γ) and averaged across all subjects for each genotype. The mean t-maps were overlaid on a T1-weighted MRI template. To visualize the direction of the effect, Met-hetero- and homozygotes were depicted separately, but were grouped together for the analyses. Images are thresholded for visualization purposes and were generated using PMOD v3.1.

Figure 4. Genotype-dependent increases in the subjective stress response.

There was a significant effect of COMT genotype on subjective stress responses, Val-homozygotes less reactive to stress than Met-hetero- and homozygotes. Increases in subjective stress responses were not significantly different for Met-hetero- and homozygotes. To visualize the direction of the effect, Met-hetero- and homozygotes were depicted separately, but were grouped together for the analyses. * = Exceeding threshold of p(corrected)<.05; n.s. = not significant.