Modulation of functional networks related to the serotonin neurotransmitter system by citalopram: Evidence from a multimodal neuroimaging study

TY - JOUR

T1 - Modulation of functional networks related to the serotonin neurotransmitter system by citalopram

T2 - Evidence from a multimodal neuroimaging study

AU - Boucherie, Daphne E

AU - Reneman, Liesbeth

AU - Booij, Jan

AU - Martins, Daniel

AU - Dipasquale, Ottavia

AU - Schrantee, Anouk

PY - 2023/12

Y1 - 2023/12

N2 - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of the serotonin 1A receptor (5-HT1AR).AIM: We investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge.METHODS: We analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [123I]FP-CIT single-photon emission computerized tomography.RESULTS: 5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low-dose group compared to the high-dose group at rest and the placebo group during the emotional face-matching task.CONCLUSIONS: Taken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.

AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of the serotonin 1A receptor (5-HT1AR).AIM: We investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge.METHODS: We analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [123I]FP-CIT single-photon emission computerized tomography.RESULTS: 5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low-dose group compared to the high-dose group at rest and the placebo group during the emotional face-matching task.CONCLUSIONS: Taken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.

KW - Humans

KW - Female

KW - Citalopram

KW - Selective Serotonin Reuptake Inhibitors/pharmacology

KW - Serotonin/metabolism

KW - Neuroimaging/methods

KW - Serotonin Plasma Membrane Transport Proteins/metabolism

U2 - 10.1177/02698811231211154

DO - 10.1177/02698811231211154

M3 - Article

C2 - 37947344

SN - 0269-8811

VL - 37

SP - 1209

EP - 1217

JO - Journal of psychopharmacology (Oxford, England)

JF - Journal of psychopharmacology (Oxford, England)

IS - 12

ER -