Abstract
Although psychotropic drugs act on neurons and glial cells, how glia respond, and whether glial responses are involved in therapeutic effects are poorly understood. Here, we show that fluoxetine (FLX), an anti-depressant, mediates its anti-depressive effect by increasing the gliotransmission of ATP. FLX increased ATP exocytosis via vesicular nucleotide transporter (VNUT). FLX-induced anti-depressive behavior was decreased in astrocyte-selective VNUT-knockout mice or when VNUT was deleted in mice, but it was increased when astrocyte-selective VNUT was overexpressed in mice. This suggests that VNUT-dependent astrocytic ATP exocytosis has a critical role in the therapeutic effect of FLX. Released ATP and its metabolite adenosine act on P2Y11 and adenosine A2b receptors expressed by astrocytes, causing an increase in brain-derived neurotrophic factor in astrocytes. These findings suggest that in addition to neurons, FLX acts on astrocytes and mediates its therapeutic effects by increasing ATP gliotransmission.
Highlights
Depression is a major public health problem worldwide
To investigate whether the antidepressant FLX increases extracellular ATP in astrocytes, primary cultures of hippocampal astrocytes were stimulated with FLX
There was no significant difference in basal immobility time when tested before and after saline administration among any mutant mice used in these studies (WT, litter mate control mice, astro-vesicular nucleotide transporter (VNUT)-KO mice and astro-VNUT-OE mice). These findings strongly suggest that FLX acts on astrocytes to control VNUT-dependent ATP exocytosis, which mediates its therapeutic effect, at least in part
Summary
Depression is a major public health problem worldwide. About 350 million people suffer from the disease and it will be ranked the second leading cause of death by the year 2020 [49]. There are several effective treatments for depression, but it is estimated that one-third of depressed patients do not respond adequately to conventional antidepressant drugs. The slow onset of their therapeutic effects restricts antidepressant use. There is an urgent need to identify the biological mechanism of depression and the pharmacological action of antidepressants. It is thought that antidepressants mediate their therapeutic effects by acting on neurons especially monoaminergic neurons, but they act on non-neuronal cells such as glial cells. To date, how glial cells respond to antidepressants or whether glial responses are involved in the therapeutic effects of antidepressants remains unknown
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