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Abstract
Background: Although endoplasmic reticulum (ER) stress caused by cocaine is becoming more widely acknowledged, its neuronal specificity and functional importance are yet unknown. Cocaine-induced ER stress may affect metabolic pathways connected to cellular stress signaling since the ER is a key location for lipid and sphingolipid production. Here, we aimed to characterize the downstream effects and cell-type specificity of cocaine- induced ER stress in the nucleus accumbens (NAc).
Methods: We administered cocaine together with assays of sphingolipid production in the NAc, immune histochemical and molecular profiling of ER stress pathways, and ultrastructural investigation of ER morphology. Additionally, we performed D1-MSN-specific knockdown of Atf4 and Sptlc1 to examine their contributions to cocaine-induced behavioral and neuroplastic changes, as well as the impacts of pharmacological suppression of ER stress and sphingolipid production.
Results: In medium spiny neurons (MSNs) that express dopamine receptor 1 (D1), cocaine specifically triggered ER stress, which was indicated by the expression of activating transcription factor 4 (ATF4). Additionally, cocaine increased the expression of serine palmitoyl transferase long-chain base subunit 1 (SPTLC1), and promoter analysis with functional validation revealed that ATF4 directly targets Sptlc1. Thus, sphingolipid metabolism remodeling was associated with ATF4 activation. Cocaine-induced behavioral and neuroplastic change was significantly lessened by blocking ER stress or sphingolipid production, as well as D1-MSN-specific reduction of Atf4 or Sptlc1.
Discussion: These results point to a possible treatment target for cocaine addiction by identifying a D1-MSN ER stress response that facilitates cocaine-induced neuro adaptations via the ATF4–SPTLC1 signaling axis.