Termination of antidepressant therapy often has negative consequences. Although symptoms of antidepressant withdrawal are widely recognized, the molecular processes that underlie them are not well characterized. We show that certain aspects of Gα_s signaling remain suppressed after antidepressant withdrawal, even after others have reverted to baseline. Antidepressant treatment causes translocation of Gα_s protein from lipid rafts to nonraft membrane regions. This results in augmented Gα_s signaling, including facilitated activation of adenylyl cyclase and increased cAMP accumulation. Using CC6 or SK-N-SH cells and a lipid raft–localized cAMP sensor, we show that Gα_s signaling is reduced in lipid rafts, even while signaling is enhanced elsewhere in the cell. These signaling changes mirror the changes in Gα_s localization observed after antidepressant treatment. Furthermore, we show that suppression of Gα_s signaling in lipid rafts persists at least 24 hours after cessation of antidepressant treatment. Gα_s localization was quantified after membrane isolation and sequential detergent extraction. We show that suppression of lipid raft Gα_s signaling persists for an extended time period after antidepressant withdrawal, whereas increased nonraft membrane Gα_s signaling reverts partially or fully upon cessation of antidepressant treatment. Translocation of Gα_s out of lipid rafts is also persistent. These events may reflect cellular adaptations to antidepressant treatment that contribute to antidepressant discontinuation syndromes and may aid in the discovery of new treatments and strategies to mitigate the symptoms of depression and antidepressant withdrawal.

中文翻译：

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抗抑郁药在停药后在脂筏中产生持续的 Gαs 相关信号变化

终止抗抑郁治疗通常会产生负面影响。尽管抗抑郁药戒断症状已被广泛认可，但其背后的分子过程并未得到很好的表征。我们表明 G α _s信号的某些方面在抗抑郁药戒断后仍然受到抑制，即使其他方面已经恢复到基线。抗抑郁药治疗导致 G α _s蛋白从脂筏转移到非脂筏膜区域。这导致 G α _s信号增强，包括促进腺苷酸环化酶的激活和增加 cAMP 积累。使用 CC6 或 SK-N-SH 细胞和脂筏定位的 cAMP 传感器，我们表明 G α _s信号在脂筏中减少，即使信号在细胞其他地方增强。这些信号变化反映了抗抑郁治疗后观察到的G α _s定位的变化。此外，我们表明，在停止抗抑郁药治疗后至少 24 小时，脂筏中 G α _s信号的抑制持续存在。G α _s定位在膜分离和连续洗涤剂提取后量化。我们表明，在停用抗抑郁药后，脂筏 G α _s信号的抑制持续了很长一段时间，而非筏膜 G α _s增加停止抗抑郁药治疗后，信号会部分或完全恢复。G α _s从脂筏中的易位也是持久的。这些事件可能反映了细胞对抗抑郁药治疗的适应，导致抗抑郁药停药综合征，并可能有助于发现新的治疗方法和策略，以减轻抑郁症和抗抑郁药戒断症状。