Abstract
Decynium-22 (D-22) is an inhibitor of the uptake2 system of monoamine clearance, resulting in increased levels of dopamine and norepinephrine (and in some cases serotonin) in the nervous system and elsewhere. Uptake2 is mediated by low-affinity, high-capacity transporters that are inhibited by glucocorticoids, suggesting a mechanism of fast glucocorticoid-monoamine interaction in the brain and a possible target for antidepressants. D-22 dose-dependently increased anxiety-like behavior in adult zebrafish exposed to the light/dark test, monotonically increasing scototaxis (dark preference), but affecting risk assessment with an inverted-U-shaped response. These results suggest that the uptake2 system has a role in defensive behavior in zebrafish, presenting a novel mechanism by which stress and glucocorticoids could produce fast neurobehavioral adjustments in vertebrates.
Highlights
Clearance of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT) released in the synaptic cleft is executed by two distinct mechanisms, uptake1 and uptake2 [1,2,3,4,5]
I show that D-22 dose-dependently increases anxiety-like behavior in the zebrafish light/dark test (LDT). These results suggest that uptake2 is present in this species, and that it functions as a mediator of stress and defensive behavior
The LDT has been proposed as a screening test for anxiolyticlike and anxiogenic-like effects of treatments in adult zebrafish [66]
Summary
Clearance of the monoamine neurotransmitters dopamine (DA), norepinephrine (NE), and serotonin (5-HT) released in the synaptic cleft is executed by two distinct mechanisms, uptake and uptake2 [1,2,3,4,5]. Uptake is mediated by high-affinity, low-capacity transporters which include the NE transporter (SLC6A2, NET), the DA transporter (SLC6A3, DAT), and the serotonin transporter (SCL6A4, SERT)[6,7]. This SLC6A family has been implicated in the pathophysiology of mental disorders, including alterations of anxiety [8,9,10,11], and are the target for major classes of anxiolytic drugs, including tricyclic antidepressants, selective 5-HT reuptake inhibitors, and 5-HT-NE reuptake inhibitors [12]. While decynium-22 (D-22), an uptake inhibitor [4], had no behavioral effect by itself, co-treatment with fluvoxamine produced synergistic effects on 5-HT clearance and immobility in the forced swimming test [23]
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