Impact of specific serotonin receptor modulation on restricted repetitive behaviors

Abstract

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.

Ultraslow serotonin oscillations in the hippocampus delineate substates across NREM and waking

“…Despite this link between 5-HT activity and locomotion in the hippocampus, it remains puzzling that the EMG signal, which reflects spontaneous and irregular movement, was observed in our data to be consistently coupled to the infraslow 5-HT oscillation. While the literature linking 5-HT and repetitive movements could shed more light on the question (51,52), further studies examining the link between hippocampal 5-HT and movement are required to clarify this relationship.…”

The Use of Compounds Derived from Cannabis sativa in the Treatment of Epilepsy, Painful Conditions, and Neuropsychiatric and Neurodegenerative Disorders

“…This inhibition of dopamine release by CB2 receptors helps regulate motor movements and reduce the frequency of repetitive behaviors. Activation of 5-HT receptors, specifically 5-HT2A/2C receptors, can induce repetitive behaviors [ 249 ]. Loss of functional CB2 receptors leads to increased repetitive behaviors following 5-HT2A/2C receptor activation, suggesting a regulatory role for CB2 receptors in this process [ 250 ].…”

Identification of an Antagonist Targeting G Protein and β-Arrestin Signaling Pathways of 5-HT7R

“…ASD is a complex neurodevelopmental and neuropsychiatric disorder characterized by deficits in social communication and the manifestation of restricted/repetitive behaviors . ASD is intricately linked to impairments of neurogenesis, synaptic pruning, and synaptic plasticity. − ASD is often accompanied by secondary disorders such as seizure, depression, anxiety, and hyperactivity. − Diagnosing and treating ASD pose substantial challenges due to heterogeneity of symptoms, varying degrees of severity, comorbidity, and incomplete understanding of etiology. − ASD arises from a complex interplay of genetic and environmental factors, including epigenetic factors, gene polymorphism, viral infections, metabolic dysfunction, and dysfunction of neurotransmitters in the brain, such as serotonin, glutamate, and acetylcholine. , Studies of neurotransmitter dysfunction in the context of ASD have been consistently reported, and among these, the modulation of serotonin receptors has emerged as a factor associated with social deficits and repetitive behaviors. ,− …”