Selective dopamine transporter inhibition with CE-123 promotes fear extinction and remodels the basolateral amygdala proteome after fear conditioning in adolescent male rats

ABSTRACT: Persistent fear responses and impaired fear extinction are hallmark features of stress-related disorders. Dopaminergic signalling within amygdala-centred circuits contributes to these processes, yet the molecular mechanisms through which dopamine regulates fear extinction remain incompletely understood. Here, we investigated whether selective inhibition of the dopamine transporter (DAT) with CE-123, a non-psychostimulant dopaminergic modulator, facilitates extinction of conditioned fear and alters associated molecular adaptations in the brain.Using an auditory fear-conditioning paradigm, adolescent male rats were exposed to repeated footshocks and subsequently underwent extinction training. Rats subjected to fear conditioning displayed persistent freezing responses during extinction and increased anxiety-like behaviour compared with control animals. Repeated administration of CE-123 during extinction training significantly reduced freezing behaviour in conditioned rats without affecting behavioural performance in controls.To identify the underlying molecular mechanisms, quantitative proteomic analyses were performed in the basolateral amygdala (BLA) and hippocampus (HPC). Fear conditioning induced extensive proteomic remodelling selectively in the BLA, involving proteins associated with glutamatergic synaptic transmission, postsynaptic signalling, and axonal plasticity, whereas the hippocampal proteome remained largely unchanged. CE-123 produced state-dependent molecular effects within the BLA, suppressing proteins related to mitochondrial ATP synthesis in control animals while enhancing ribosomal, mitochondrial, and RNA-processing pathways in fear-conditioned rats, consistent with adaptive molecular plasticity accompanying extinction learning.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain

SUBMITTER: Piotr Suder  

LAB HEAD: Piotr Suder

PROVIDER: PXD075812 | Pride | 2026-10-05

REPOSITORIES: Pride