Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

Abstract

In the search for antidepressants' (ADs') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI-and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis.

Accumulation of an Antidepressant in Vesiculogenic Membranes of Yeast Cells Triggers Autophagy

“…We argue that autophagy mitigates cationic amphipath accumulation in cellular membranes. This interpretation is supported by a recent study that documented induction of autophagy by antidepressants in mammalian neuronal cell lines [35]. Autophagy may be one of several buffering systems that evolved to preserve cellular membrane homeostasis in the face of endogenous (or exogenous) charged amphipath accumulation, but when sertraline-induced membrane curvature stresses become too punishing at high or sustained doses, cytotoxicity ensues [36].…”

Association of FKBP51 with Priming of Autophagy Pathways and Mediation of Antidepressant Treatment Response: Evidence in Cells, Mice, and Humans

“…Each antidepressant was used at 10 µM, the concentration that proved sufficient for induction of autophagy markers in cell culture (Figure S4 and [14]). Treatment with PAR increased the amount of Akt and Beclin1 co-precipitating with FKBP51 (Akt, p  = 0.014; Beclin1, p  = 0.012; Figures 3A and S5A).…”

“…We analyzed whether these pathways involve autophagic events based on reports stating that some antidepressants alter at least the initial processes of autophagy [14],[15]. Given that FKBP51 can act via the central chaperone Hsp90, which controls several kinases including the autophagy regulators Akt and Beclin1 [16], intracellular autophagic events appeared more likely than membrane targets of antidepressants to be co-regulated by FKBP51.…”

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

“…The antidepressant drug amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) have been reported to increase the expression of the autophagic markers LC3-II and beclin1, but venlafaxine fails to exert these effects [65] . AMI-and CIT-induced autophagy is functional in terms of autophagic fl ux, and is partially mediated by class III PI3K-and ROS-dependent pathways [62] .…”