“
“Serotonin (5-HT) PARP inhibitor signaling in the central nervous system (CNS) helps to regulate a variety of important cognitive and behavioral processes and it is a common therapeutic target for mood disorders. Because sleep abnormalities are frequently associated

with mood disorders, there has been substantial interest in the regulatory abilities of 5-HT signaling on the sleep/wake cycle. However, to date there have been few practical and reliable ways to reversibly manipulate brain 5-HT levels without disrupting other monoaminergic signaling pathways that may be important for sleep. In this issue of European Journal of Neuroscience, Nakamaru-Ogiso and colleagues reveal a new method for reducing brain 5-HT levels in rats, a well-established Ferroptosis tumor rodent model of sleep–wake architecture. Intraperitoneal injections of the hemoprotein enzyme tryptophan side chain oxidase I (TSOI) transiently reduce brain and peripheral 5-HT concentrations by reversibly depleting the rats of tryptophan, while preserving catecholeaminergic

signaling. The authors report that this transient reduction of brain 5-HT abolishes the sleep/wake rhythm but has no meaningful influences on daily sleep amount. Moreover, the circadian rhythm in brain temperature is preserved in TSOI-injected rats, providing evidence that the effects of the manipulation are specific to sleep and are not caused by global effects on circadian timing. These findings suggest that in addition to its well-established Cediranib (AZD2171) regulatory influences

on central circadian timing, brain 5-HT also plays a more direct role in the specific regulation of the sleep/wake rhythm. The lack of practical methods to rapidly and reversibly manipulate brain 5-HT in mammals has been an obstacle in our understanding of the role of 5-HT signaling in sleep. Tryptophan-hydroxylase 2 (TPH2), the rate-limiting enzyme in 5-HT synthesis in the brain, has been a dependable target for brain 5-HT reduction; however, a lack of specificity of TPH2 inhibitors results in the collateral reduction of catecholamines such as the sleep/wake regulator norepinephrine, making these types of agents impractical for sleep studies. Serotonergic neurotoxins and TPH2 molecular deletions in mice have also been valuable to uncover the specific roles of 5-HT signaling, but neither manipulation is reversible, giving them limited usefulness in in vivo sleep experiments. Nakamaru-Ogiso and colleagues report that TSOI eliminates tryptophan and reduces brain 5-HT levels to 30% of controls within 12 h of treatment, with no collateral reductions in catecholeamines, other amino acids or protein synthesis. These influences of TSOI injection are no longer observed 96 h after injection.