Abstract
Termination of antidepressant therapy often has negative consequences. While symptoms of antidepressant withdrawal are widely recognized, the molecular processes that underlie them are not well characterized. We show that certain aspects of Gαs signaling remain suppressed following antidepressant withdrawal, even after others have reverted to baseline. Antidepressant treatment causes translocation of Gαs protein from lipid rafts, to non-raft membrane regions. This results in augmented Gαs signaling, including facilitated activation of adenylyl cyclase (AC) and increased cAMP accumulation. Using c6 or SK-N-SH cells and a lipid raft localized cAMP sensor, we show that Gαs signaling is reduced in lipid rafts, even while signaling is enhanced elsewhere in the cell. These signaling changes mirror the changes in Gαs localization observed following antidepressant treatment. Furthermore, we show that suppression of Gαs signaling in lipid rafts persists at least 24 hr after cessation of antidepressant treatment. Gαs localization was quantified following membrane isolation and sequential detergent extraction. We show that suppression of lipid raft Gαs signaling persists for an extended time period after antidepressant withdrawal, while increased non-raft membrane Gαs signaling reverts partially or fully upon cessation of antidepressant treatment. Translocation of Gαs out of lipid rafts is also persistent. These events may reflect cellular adaptations to antidepressant treatment which contribute to antidepressant withdrawal syndromes, and may aid in the discovery of new treatments and strategies to mitigate these side effects.
Significance Statement This work explores, for the first time, the effects of antidepressants on Gαs signaling following drug withdrawal. This provides novel insight into the cellular and molecular processes affected by antidepressant drugs, and their persistence after discontinuation of treatment.
- Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics