5-HT1A receptor x 5-HT6 receptor x 5-HT2C receptor x 5-HT2A receptor

Depression increases the risk of breast cancer recurrence and metastasis. However, there lacks potential biomarkers for predicting prognosis in breast cancer. 5-hydroxytryptamine (5-HT) plays a key role in the pathogenesis and treatment of depression. In this study, we developed a prognostic signature based on 5-HT receptors (5-HTRs) and elucidated its potential immune regulatory mechanisms for breast cancer prognosis.

Oncomine, GEPIA, UALCAN, cBioPortal, Kaplan-Meier plotter, and TIMER were used to analyze differential expression, prognostic value, genetic alteration, and immune cell infiltration of HTRs in breast cancer patients. The model training and validation assays were based on the analyses of GSE1456 and GSE86166. A risk signature was established by univariate and multivariate Cox regression analyses. The transwell assay was utilized to verify the effect of the 5-HTRs expression on breast cancer invasion. Effects of HTR2A/2B inhibitor on CD8⁺ T cell proliferation and infiltration as well as apoptosis of 4T1 cells in the tumor microenvironment were detected by flow cytometry and TUNEL assay. Zebrafish and mouse breast cancer xenografts were used to determine the effect of HTR2A/2B inhibitor on breast cancer metastasis.

The expression levels of HTR1A, HTR1B, HTR2A, HTR2B, HTR2C, HTR4, and HTR7 were significantly downregulated in highly malignant breast cancer types. 5-HTRs were significantly associated with recurrence-free survival (RFS) in breast cancer patients. The genetic alteration of HTR1D, HTR3A, HTR3B, and HTR6 in breast cancer patients was significantly associated with shorter overall survival (OS). Finally, HTR2A and HTR2B were determined to construct the risk signature. The expression of HTR2A/2B was positively correlated with the infiltration of immune cells such as CD8⁺ T cells and macrophages. Furthermore, inhibition of HTR2A expression could suppress CD8⁺ T cell proliferation and enhance invasion and metastasis of breast cancer cells in both zebrafish and mice model.

The HTR2A/2B risk signature not only highlights the significance of HTRs in breast cancer prognosis by modulating cancer immune microenvironment, but also provides a novel gene-testing tool for early prevention of depression in breast cancer patients and lead to an improved prognosis and quality of life.

Restricted, repetitive behaviors (RRBs) are commonly divided into two behavioral categories, lower-order and higher-order RRBs. Individuals displaying lower-order motoric RRBs may express repetitive hand flapping behaviors, body rocking back and forth movements, and continuous body spinning. Higher-order RRBs most commonly cover the behavior inflexibility and cognitive rigidity commonly found in disorders such as autism spectrum disorder and obsessive-compulsive disorder. Various neuropsychiatric disorders are plagued by RRBs yet no FDA-approved treatments have been identified. In rodents, lower-order RRBs are commonly measured through various tasks, such as repetitive self-grooming, marble burying, and stereotypic motor behaviors. This review focuses on the effects that modulation of specific serotonin receptors have on lower-order RRBs. Although there is research examining how changes in 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptor modulation, more research has focused on the 5-HT1A, 5-HT2A, and 5-HT2C receptors. The accumulating data suggest that increasing 5-HT1A activation decreases RRBs while blocking 5-HT1A activation has no effect on RRBs. While there are mixed findings regarding the impact of 5-HT2A modulation on RRBs, the general trend shows mixed effects of 5-HT2A receptor activation RRB expression, whereas blockade generally decreases RRBs. 5-HT2C receptor activation can modulate RRBs in either direction depending on the 5-HT2C drug used, blocking 5-HT2C activation only seems to show therapeutic properties when 5-HT2C activation is already elevated. The other 5-HT receptors have been explored far less but show promise as potential targets for regulating RRBs. Although it is less clear due to the involvement of 5-HT1D, 5-HT1A activation increases RRBs, and blocking 5-HT1A tends to decrease RRBs. 5-HT2B activation could reduce RRBs, while inhibiting 5-HT2B does not impact RRBs. Increasing 5-HT3 has not been shown to affect RRBs. Yet, increases in RRBs have been observed in Htr3a KO mice. 5-HT6 receptor activation can increase RRBs, while blocking 5-HT6 activity tends to decrease RRBs. Lastly, neither increasing or blocking 5-HT7 activity can reduce RRBs. In sum, there is no uniform pattern in whether all specific 5-HT receptors affect RRBs in either direction, instead, there is evidence suggesting that different 5-HT receptors can modulate RRBs in different directions. Further researching the less explored receptors and aiming to understand why these receptors can differently modulate RRBs, may play a key role in developing therapeutics that treat RRBs.

The constitutive activity of different serotonin receptors (5-HTRs) toward intracellular signaling pathways has been proposed to have physiological and pathological importance. Inverse agonists block the constitutive activity and can be used to probe and silence such a spontaneous activity. The constitutive activity of 5-HTRs can be observed in various heterologous systems of expression in vitro (very high for 5-HT_2CR; very low for 5-HT_2AR). The demonstration of the existence of this activity in native tissues and ultimately in integrative neurobiology and behavior is a real pharmacological challenge. Irrespective of the existence of mutants or polymorphisms that could alter the constitutive activity of 5-HTRs, evidence suggests that spontaneous activity of 5-HT_2CR could impact the activity of neurobiological networks and that of 5-HT₆R and 5-HT₇R the developmental morphogenesis. Some findings exist for 5-HT_2BR and 5-HT_2AR in diverse though rare conditions. The existence of a constitutive activity for 5-HT_1AR, 5-HT_1B/1DR, and 5-HT₄R is still poorly supported. When identified, the constitutive activity may differ according to brain location, state of activity (phasic in nature), and intracellular signaling pathways. A very few studies have reported aberrant constitutive activity of 5-HTRs in animal models of human diseases and patients. The purpose of this review is a critical examination of the available neuropharmacological data on the constitutive activity of 5-HTRs to determine whether this activity is an essential component of the serotonergic system transmission and it may be a possible target for CNS drug development.