Fluctuations in [11C]SB207145 PET Binding Associated with Change in Threat-Related Amygdala Reactivity in Humans

Abstract

Serotonin critically affects the neural processing of emotionally salient stimuli, including indices of threat; however, how alterations in serotonin signaling contribute to changes in brain function is not well understood. Recently, we showed in a placebo-controlled study of 32 healthy males that brain serotonin 4 receptor (5-HT4) binding, assessed with [(11)C]SB207145 PET, was sensitive to a 3-week intervention with the selective serotonin reuptake inhibitor fluoxetine, supporting it as an in vivo model for fluctuations in central serotonin levels. Participants also underwent functional magnetic resonance imaging while performing a gender discrimination task of fearful, angry, and neutral faces. This offered a unique opportunity to evaluate whether individual fluctuations in central serotonin levels, indexed by change in [(11)C]SB207145 binding, predicted changes in threat-related reactivity (ie, fear and angry vs neutral faces) within a corticolimbic circuit including the amygdala and medial prefrontal and anterior cingulate cortex. We observed a significant association such that decreased brain-wide [(11)C]SB207145 binding (ie, increased brain serotonin levels) was associated with lower threat-related amygdala reactivity, whereas intervention group status did not predict change in corticolimbic reactivity. This suggests that in the healthy brain, interindividual responses to pharmacologically induced and spontaneously occurring fluctuations in [(11)C]SB207145 binding, a putative marker of brain serotonin levels, affect amygdala reactivity to threat. Our finding also supports that change in brain [(11)C]SB207145 binding may be a relevant marker for evaluating neurobiological mechanisms underlying sensitivity to threat and serotonin signaling.

5‐HTTLPR differentially predicts brain network responses to emotional faces

“…All participants were recruited from the Copenhagen region via online advertisements for research projects approved by the Ethics Committee of Copenhagen and Frederiksberg, Denmark (H-1-2010-091, amendments: 28633, 30043;H-1-2010-085, amendments 28641, 33540;(KF)01-2006-20, amendment: 23504, 23830). Emotional faces fMRI data from 30 [Fisher et al, 2014b] and 32 [Fisher et al, 2015] of the participants included in the current study have been described in unrelated studies. Notably, some projects recruited only males and others recruited based on 5-HTTLPR genotype status (i.e., oversampling of L A L A and S 0 S 0 individuals).…”

“…Notably, all significant genotype and emotion condition effects remained when excluding these two participants. Emotional faces fMRI data from 30 [Fisher et al, 2014b] and 32 [Fisher et al, 2015] of the participants included in the current study have been described in unrelated studies.…”

No evidence for a role of the serotonin 4 receptor in five-factor personality traits: A positron emission tomography brain study

“…From animal studies there is evidence that 5-HT 4 R binding potential (BP ND ) is inversely related to 5-HT tonus [ 34 , 35 ], which has been supported by subsequent genetic [ 36 ] and pharmacological intervention [ 37 ] studies in humans. Furthermore, we have previously shown that in healthy participants, 5-HT 4 R BP ND is associated with episodic memory [ 38 , 39 ], familial risk for depression [ 40 ], threat-related reactivity of amygdala [ 41 ], which is a key brain structure underlying personality trait N [ 42 ], as well as trait aggression in healthy males [ 43 ]. Together these findings suggest that the 5-HT 4 R may be linked to stable personality characteristics which warrants further investigation.…”

Brain serotonin 4 receptor binding is inversely associated with verbal memory recall

“…Many previous studies have demonstrated changes in affective processing in response to pharmacological manipulation of 5-HT signaling (Fisher, Haahr, et al, 2015;Harmer, Bhagwagar, Cowen, & Goodwin, 2002;Harmer, Shelley, Cowen, & Goodwin, 2004;Mendelsohn et al, 2009;Molodtsova, 2008). Therefore, the noted differences in recall of negative words compared to positive and neutral words should also be investigated targeting the 5-HT 4 R with 5-HT acting interventions.…”