ER Stress in D1-MSNs Mediates Cocaine-Induced Behavioral Plasticity via the ATF4–SPTLC1 Axis

Yue Zhao¹Shu Li¹Linhong Jiang¹Ying Zhao¹Weihong Kuang¹Qingfan Wei¹Yuanyi Zhou¹Shuang Han¹Liang Wang¹Hongchun Li¹Dai Yanping¹Xiaofeng Yang¹Siqi Xu¹Feng Qin¹Rong Chen¹Yaxing Chen¹Qian Bu²Bo Chen²Bin Liu²Meng Qin¹Yinglan Zhao¹Xiaobo Cen^1*

• ¹West China Hospital of Sichuan University, Chengdu, China
• ²WestChina Frontier Pharma Tech Co Ltd, Chengdu, China

Cocaine-induced endoplasmic reticulum (ER) stress has been increasingly recognized, yet its neuronal specificity and functional significance in addiction remain unclear. Here, we investigated the cellular specificity and downstream consequences of cocaine-induced ER stress in the nucleus accumbens (NAc). Our data showed that repeated cocaine administration activated ER stress in dopamine receptor 1 (D1)-expressing medium spiny neurons (MSNs), characterized by the induction of activating transcription factor 4 (ATF4). Cocaine markedly upregulated the expression of serine palmitoyl transferase long-chain base subunit 1 (SPTLC1), a key subunit of serine palmitoyl transferase that controls de novo synthesis of sphingolipids within ER. Promoter analysis and functional validation identified Sptlc1 as a direct transcriptional target of ATF4. These adaptive responses integrated activation of ATF4 and remodeled sphingolipid metabolism. Notably, both pharmacological inhibition of ER stress/SPTLC1 and D1-MSNs–specific knockdown of Atf4 or Sptlc1 repressed cocaine-induced neurobehaviors and neuroplasticity. Collectively, our findings reveal a D1-MSN ER stress response that promotes cocaine-induced neuroadaptations via the ATF4–SPTLC1 signaling axis, providing a potential therapeutic target for cocaine addiction.