Selective Dopamine Transporter Inhibition with CE-123 Promotes Fear Extinction and Alters the Basolateral Amygdala Proteome Following Fear Extinction in Adolescent Male Rats
4 affiliations
- 1Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Chodzki 4a st., 20-093 Lublin, Poland
- 2Department of Analytical Chemistry and Biochemistry, Faculty of Materials Sciences and Ceramics, AGH University of Krakow, Mickiewicza 30 Avenue, 30-059 Krakow, Poland
- 3Experimental Medicine Center, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland
- 4Department of Neuroproteomics, Paracelsus Medical University, 5020 Salzburg, Austria
Abstract
Persistent fear responses and impaired fear extinction are characteristic features of stress-related disorders. Dopaminergic signalling within amygdala-centred circuits contributes to fear extinction, but the associated molecular mechanisms remain unclear. Here, we investigated whether selective dopamine transporter (DAT) inhibition with CE-123 (10 mg/kg, intraperitoneally) facilitates fear extinction and induces region-specific molecular adaptations. Adolescent male rats were subjected to a modified stress-enhanced fear learning (SEFL)-like paradigm followed by extinction training. Rats exposed to high-intensity fear conditioning (STRESSED groups) displayed persistent freezing and increased anxiety-like behaviour compared with non-shocked controls (NON-STRESSED groups). Repeated CE-123 administration during extinction significantly reduced freezing in stressed rats without affecting non-stressed animals. Quantitative proteomic analyses of the basolateral amygdala (BLA) and hippocampus (HPC) revealed marked region-specific effects. Stress-related fear enhancement induced extensive proteomic remodelling in the BLA, involving proteins associated with glutamatergic signalling, synaptic plasticity, and axonal organization, whereas the hippocampal proteome was largely unaffected. CE-123 also produced BLA-specific molecular effects, reducing the abundance of proteins associated with mitochondrial ATP synthesis in non-stressed animals and with ribosomal, mitochondrial, and RNA-processing pathways in stressed rats. These findings identify the BLA as a key substrate of fear-related molecular adaptations and demonstrate that selective DAT inhibition modulates amygdala proteomic architecture during fear extinction. Overall, the results support further investigation of DAT modulation as a potential strategy for facilitating fear extinction in stress-related disorders.
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BibTeX
@article{grochecki2026selective,
title = {{Selective Dopamine Transporter Inhibition with CE-123 Promotes Fear Extinction and Alters the Basolateral Amygdala Proteome Following Fear Extinction in Adolescent Male Rats}},
author = {Pawel Grochecki and Malgorzata Hopcias and Justyna Lubinska and Tymoteusz Slowik and Gert Lubec and Joanna Listos and Piotr Suder and Jolanta H. Kotlinska},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188352},
url = {https://www.mdpi.com/1422-0067/27/18/8352},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Selective Dopamine Transporter Inhibition with CE-123 Promotes Fear Extinction and Alters the Basolateral Amygdala Proteome Following Fear Extinction in Adolescent Male Rats
AU - Pawel Grochecki
AU - Malgorzata Hopcias
AU - Justyna Lubinska
AU - Tymoteusz Slowik
AU - Gert Lubec
AU - Joanna Listos
AU - Piotr Suder
AU - Jolanta H. Kotlinska
PY - 2026
DA - 2026/09/19
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188352
UR - https://www.mdpi.com/1422-0067/27/18/8352
AB - Persistent fear responses and impaired fear extinction are characteristic features of stress-related disorders. Dopaminergic signalling within amygdala-centred circuits contributes to fear extinction, but the associated molecular mechanisms remain unclear. Here, we investigated whether selective dopamine transporter (DAT) inhibition with CE-123 (10 mg/kg, intraperitoneally) facilitates fear extinction and induces region-specific molecular adaptations. Adolescent male rats were subjected to a modified stress-enhanced fear learning (SEFL)-like paradigm followed by extinction training. Rats exposed to high-intensity fear conditioning (STRESSED groups) displayed persistent freezing and increased anxiety-like behaviour compared with non-shocked controls (NON-STRESSED groups). Repeated CE-123 administration during extinction significantly reduced freezing in stressed rats without affecting non-stressed animals. Quantitative proteomic analyses of the basolateral amygdala (BLA) and hippocampus (HPC) revealed marked region-specific effects. Stress-related fear enhancement induced extensive proteomic remodelling in the BLA, involving proteins associated with glutamatergic signalling, synaptic plasticity, and axonal organization, whereas the hippocampal proteome was largely unaffected. CE-123 also produced BLA-specific molecular effects, reducing the abundance of proteins associated with mitochondrial ATP synthesis in non-stressed animals and with ribosomal, mitochondrial, and RNA-processing pathways in stressed rats. These findings identify the BLA as a key substrate of fear-related molecular adaptations and demonstrate that selective DAT inhibition modulates amygdala proteomic architecture during fear extinction. Overall, the results support further investigation of DAT modulation as a potential strategy for facilitating fear extinction in stress-related disorders.
SN - 1422-0067
ER -