The results of the present study suggest that DRD2 rs1076560 genotype is associated with specific parameters of emotion processing. At the behavioral level, there was a specific effect within the emotion stability dimension of the BFQ. In particular, GG subjects had reduced emotion control scores relative to GT subjects. Furthermore, GG subjects were slower when explicitly processing facial stimuli. The fMRI data indicated that GG subjects had greater left amygdala activity during implicit processing and greater left DLPFC signal during explicit processing of facial expressions. Consistently, activity in DLPFC of GG subjects was correlated with ratings of the emotional impact of facial stimuli presented during the task. Furthermore, DRD2 rs1076560 genotype and facial expressions were differentially associated with functional connectivity of medial prefrontal areas with amygdala during implicit processing and with DLPFC during explicit processing. In particular, GG individuals had negative PPI while evaluating emotionally charged faces, while PPI was positive in GT subjects. On the other hand, processing of neutral expressions was associated with the opposite pattern. Behavioral relevance of these data is further suggested by analysis of the relationship between amygdala/DLPFC medial prefrontal cortex functional connectivity during processing of emotionally charged faces and emotion control scores which indicated significant positive correlations in GT subjects only.
Studies in animal models have indicated that dopamine D2 receptor signaling is involved in emotional behavior (Gendreau et al., 1998
; Guarraci et al., 2000
; Greba et al., 2001
) and in activity of amygdala and prefrontal cortex, brain regions centrally implicated in emotion processing (Levey et al., 1993
; Rosenkranz and Grace, 2001
; Seamans and Yang, 2004
). Of note, these brain areas are functionally connected during management of emotional inputs (Pezze and Feldon, 2004
; Stein et al., 2007
). Our results suggesting association of emotional behavior and physiology during emotion processing with genetically determined D2 signaling are consistent with these data. In particular, in GG subjects we found lower emotion control scores and lower speed of processing of emotionally relevant explicit stimuli, as well as greater amygdala and DLPFC activity respectively during implicit and explicit processing of emotionally relevant stimuli. These results may indicate that a ratio of D2 receptors favoring the presynaptic form (D2S) may predispose GG subjects to lower capacity of handling emotional inputs. In this sense, these data are consistent with previous findings in animals expressing only the D2S receptor which have greater levels of behavioral ‘anxiety’ in the form of lower level of exploration and increased latency to escape from harmful situations (Hranilovic et al., 2008
). On the other hand, lack of DRD2
rs1076560 genotype association with the impulse control scale within the emotional stability dimension of the BFQ is consistent with other studies indicating no effect of D2 signaling on impulsive behavior (van Gaalen et al., 2006; Arnsten and Li, 2005) and suggests a specific association of DRD2
rs1076560 genotype with emotion control.
The association of this DRD2
genotype with amygdala activity during implicit processing is consistent with the known role of this brain region in perception of emotionally relevant inputs (LeDoux, 1998
; Hariri et al., 2000
; Salgado-Pineda et al., 2005
) and with data suggesting involvement of D2 receptors in amygdala responses (Pezze and Feldon, 2004
). Furthermore, differential DLPFC response associated with this polymorphism during explicit processing is in line with several studies involving this brain region in emotional regulation (Phillips et al., 2003
), as well as with the well established relevance of D2 signaling in activity of prefrontal neurons (Seamans and Yang, 2004
All together, these results suggest that genetically determined D2 signaling is associated with task and region specific effects. In fact, the two DRD2
rs1076560 genotype groups have differential BOLD responses in amygdala and DLPFC during tasks in which these brain regions are more specifically involved, i.e. implicit emotion perception and explicit emotional evaluation, respectively. Furthermore, specificity of the present results for the emotional domain is also suggested by our previous data on association of brain activity with DRD2
rs1076560 genotype during cognition. In particular, differential activity between GG and GT subjects in striatum and DLPFC was found during working memory. However, the results of that study were in the opposite direction, with greater BOLD responses in GT subjects relative to GG individuals (Zhang et al., 2007
). In this respect, the present data are consistent with those reported in other studies investigating the COMT Val158
Met (rs4680) polymorphism revealing pleiotropic opposite effects in the cognitive and emotional domains (Blasi et al., 2005
; Smolka et al., 2005
rs1076560 polymorphism was also associated with opposite effects on functional connectivity between amygdala and DLPFC with medial prefrontal regions during implicit and explicit processing of emotionally and non-emotionally charged facial expressions. During both emotional processes investigated with our task, positive PPI values (i.e., a positive relationship between activity in amygdala and in DLPFC with that in medial prefrontal regions) were found in GT subjects while evaluating emotionally charged facial expressions, whereas they were negative (i.e., the opposite as before) in GG individuals. Of note, these medial prefrontal regions had overlapping spatial location during both implicit and explicit processing. Previous studies have associated dorsal regions of the medial prefrontal cortex with processing of emotional stimuli. For example, fMRI studies have indicated involvement of these medial brain areas in reappraisal of stimuli with negative valence (Ochsner et al., 2004b
), attention to own emotional response to external stimuli (Gusnard et al., 2001
), regulation of negative emotions (Ochsner et al., 2004a
), cognitive evaluation of emotional stimuli (Rubino et al., 2007
). Therefore, the results of the present study suggest that functional connections between relevant nodes of the emotional network such as the medial prefrontal cortex, the amygdala and the DLPFC during different emotional processes may be associated with genetically determined dopamine signaling. Furthermore, GT subjects had positive correlations between amygdala/DLPFC functional connections with medial prefrontal regions and emotion control scores, while no such relationship was present in GG individuals. These results are in line with other studies showing effects of genetically determined modulation of dopamine signaling on the relationship between physiology and behavior (Drabant et al., 2006
). Moreover, they suggest that variations in dopamine signaling related with the DRD2
rs1076560 polymorphism may be implicated in changes of functional connections within the emotional network and in their impact on processing of emotionally salient stimuli.
Interestingly, the results of the present study vary with regard to their specificity for emotionally charged stimuli. For example, there was no interaction of BOLD effects with facial expression, which was instead associated with PPI effects. Differential effects of specific variables on either activity of discrete brain regions or brain functional coupling is not new in the fMRI literature (for e.g. (Williams et al., 2006
; Meyer-Lindenberg, 2009
; Prata et al., 2009
)). Some recent studies have also reported no effect of genotype on regional brain activation along with very robust effects on PPI (Esslinger et al., 2009
). Another factor that may be associated with these differences is that perception of different facial expressions may involve greater functional integration of activity of different brain regions. Therefore, the physiological factors associated with such processing may more likely and more strongly affect measures of functional coupling in some brain regions.
A limitation of this study is that the present data do not allow us to clarify the relevance of the examined variant for the risk architecture of psychiatric disorders, as neither evidence for an association of these particular phenotypes with patient populations, nor evidence for their heritability is provided. However, investigation of these phenotypes in patient populations was beyond the aim of this work.
In conclusion, all these data indicate that genetic variation in DRD2 modulating D2 pre- vs. post-synaptic signaling are relevant to specific aspects of behavior and physiology during emotion processing. Further studies are needed to elucidate the role of DRD2 rs1076560 in brain disorders with relevant emotional deficits, including schizophrenia, depression, and anxiety disorders.