TY - JOUR
T1 - A serotonergic biobehavioral signature differentiates cocaine use disorder participants administered mirtazapine
AU - Ma, Liangsuo
AU - Cunningham, Kathryn A.
AU - Anastasio, Noelle C.
AU - Bjork, James M.
AU - Taylor, Brian A.
AU - Arias, Albert J.
AU - Riley, Brien P.
AU - Snyder, Andrew D.
AU - Moeller, F. Gerard
N1 - Funding Information:
This work was financially supported by National Institute on Drug Abuse (NIDA) grants U54 DA038999 (FGM) and P50 DA033935 (KAC), and the Center for Addiction Research at the University of Texas Medical Branch, as well as UL1TR002649 (FGM) which supports the imaging infrastructure for VCU. We would like to extend our gratitude to those participants recruited into this study and to our research teams for adherence to study design and recruitment efforts.
Funding Information:
FGM has past research funding from Indivior Pharmaceuticals and Nektar Therapeutics for research unrelated to this study. KAC and NCA have current research funding from VidaLibreBio, Inc., for research unrelated to this study. Other authors declare no competing interests.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT2CR gene relative to a 5-HT2CR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT2CR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer “fingerprint” of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.
AB - Cocaine use disorder (CUD) patients display heterogenous symptoms and unforeseeable responses to available treatment approaches, highlighting the need to identify objective, accessible biobehavioral signatures to predict clinical trial success in this population. In the present experiments, we employed a task-based behavioral and pharmacogenetic-fMRI approach to address this gap. Craving, an intense desire to take cocaine, can be evoked by exposure to cocaine-associated stimuli which can trigger relapse during attempted recovery. Attentional bias towards cocaine-associated words is linked to enhanced effective connectivity (EC) from the anterior cingulate cortex (ACC) to hippocampus in CUD participants, an observation which was replicated in a new cohort of participants in the present studies. Serotonin regulates attentional bias to cocaine and the serotonergic antagonist mirtazapine decreased activated EC associated with attentional bias, with greater effectiveness in those CUD participants carrying the wild-type 5-HT2CR gene relative to a 5-HT2CR single nucleotide polymorphism (rs6318). These data suggest that the wild-type 5-HT2CR is necessary for the efficacy of mirtazapine to decrease activated EC in CUD participants and that mirtazapine may serve as an abstinence enhancer to mitigate brain substrates of craving in response to cocaine-associated stimuli in participants with this pharmacogenetic descriptor. These results are distinctive in outlining a richer “fingerprint” of the complex neurocircuitry, behavior and pharmacogenetics profile of CUD participants which may provide insight into success of future medications development projects.
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U2 - 10.1038/s41398-022-01934-w
DO - 10.1038/s41398-022-01934-w
M3 - Article
C2 - 35523779
AN - SCOPUS:85129713171
SN - 2158-3188
VL - 12
JO - Translational Psychiatry
JF - Translational Psychiatry
IS - 1
M1 - 187
ER -