Serotonergic and noradrenergic modulation of emotion processing by single dose antidepressants

Abstract

Serotonergic and noradrenergic pathways are the main targets of antidepressants. Their differential effects on emotion processing-related brain activation are, however, to be further characterized. We aimed at elucidating the neural sites of action of an acute differential serotonergic and noradrenergic influence on an emotion-processing task, which was earlier shown to be associated with depressiveness. In a single-blind pseudo-randomized crossover study, 21 healthy subjects (16 subjects finally included in the analysis) participated to ingest a single dose at three time points of either 40 mg citalopram, a selective serotonin-reuptake inhibitor, 8 mg reboxetine, a selective noradrenaline-reuptake inhibitor, or placebo 2-3 h before functional magnetic resonance imaging (fMRI). During fMRI, subjects performed a task comprising the anticipation and perception of pictures of either 'known' (positive, negative, neutral) or 'unknown' valence (randomly 50% positive or negative). In direct comparison with citalopram and with placebo, reboxetine increased brain activity in the medial thalamus. Citalopram modulated certain prefrontal and insular areas more prominently. Other frontal and parieto-occipital areas were modulated by both drugs. In conclusion, the functional network involved in emotional information processing could be modulated by the acute application of selective noradrenergic and serotonergic drugs revealing a noradrenergic effect in thalamic and frontal areas, and a prefrontal and insular focus of serotonergic modulation. These findings could have implications for future selection criteria concerning personalized antidepressant medication in depression.

Figure 1

Schematic summary of the paradigm for anticipation and perception of emotional stimuli. Presented are the four conditions with the respective cues indicating the valence of the following picture: ‘∪' before a ‘positive' picture, ‘∩' before a ‘negative' picture, ‘−' before a ‘neutral' picture, ‘ ∣ ' before a picture of ‘unknown' valence that could have been either positive or negative. The cue was presented for 1000 ms, followed by an anticipation period of 6920 ms (cue + anticipation=4 TR, 1 TR=1980 ms). Thereafter the respective picture was shown for 7920 ms (4 TR). Here, the cues are enlarged for presentational reasons.

Figure 2

Serotonergic modulation of brain activation during the anticipation of negative (ng) vs neutral (nt) pictures. Shown are significant brain regions in the comparison Citalopram >Placebo in bilateral DLPFC in coronal brain sections with below the respective averaged event-related time courses of BOLD response. Anticipation period between the gray bars are shown as in all figures, thereafter the perception of the respective picture. Significance level of the random effects analysis p<0.001, color bars representing t-values. R, right; L, left; y, Talairach coordinate indicating the position of the coronal section.

Figure 3

Noradrenergic modulation of brain activation during the anticipation of negative (ng) vs neutral (nt) pictures. Shown are significant brain regions in the comparison Reboxetine >Placebo in coronal brain sections with below the respective averaged event-related time courses of BOLD response. Significance level of the random effects analysis p<0.001. MPFC, medial prefrontal cortex; L, left; y, Talairach coordinate indicating the position of the coronal section.

Figure 4

Noradrenergic modulation of brain activation during the anticipation of unknown cued (uk) vs neutral (nt) pictures. Shown are significant brain regions in the comparison Reboxetine >Placebo in coronal brainsections with below the respective averaged event-related time courses of BOLD response. Significance level of the random effects analysis p<0.001. R, right; L, left; y, Talairach coordinate indicating the position of the coronal section.

Figure 5

Overview of the serotonergic (red) and noradrenergic (blue) activations during the anticipation of negatively vs neutrally cued pictures. Contrast Citalopram >Reboxetine. Shown are continuous transversal brain sections with a distance of 5 mm ranging from z=65 to z=−5. Significance level of the random effects group comparison p<0.01. R, right; L, left.

Figure 6

Direct comparison of noradrenergic and serotonergic modulation of brain activation during the anticipation of negatively (ng) and unknown cued (uk) vs neutral (nt) pictures in the medial thalamus. Shown is the significant brain region in the comparison Reboxetine >Citalopram in coronal and transversal brain sections with below the respective averaged event-related time courses of BOLD response. Significance level of the random effects analysis p<0.01. y, z, Talairach coordinate indicating the position of the sections.