The 5-HT7 receptor influences stereotypic behavior in a model of obsessive-compulsive disorder

Abstract

The 5-HT 7 receptor has been suggested as a new putative target for the treatment of neuropsychiatric disorders, especially depression. This hypothesis is based on the finding that antidepressant drugs have relatively high affinity for the 5-HT 7 receptor, and that inactivation or blockade of the receptor leads to an antidepressant-like profile in behavioral models and sleep parameters. Obsessivecompulsive disorder is also believed to involve the serotonergic system and is treated using antidepressants, thus it is of interest to study the possible role of the 5-HT 7 receptor in this disorder. We have evaluated the effect of inactivation or pharmacological blockade of the 5-HT 7 receptor in three mouse behavioral models that are believed to mimic some of the stereotypic aspects of obsessive-compulsive disorder. In the most well established behavioral model, marble burying, both inactivation and blockade of the 5-HT 7 receptor reduced stereotypic behavior in that the number of marbles buried decreased. In two newer, less well characterized models, head dipping and plasticmesh screen chewing, there was no difference between wild-type mice and mice lacking the 5-HT 7 receptor. Taken together the data confirms and expands on previous findings that the 5-HT 7 receptor is of importance for behaviors affected by antidepressants, and suggests that the 5-HT 7 receptor might be of relevance as a target for the treatment of obsessive-compulsive disorder. Keywordsserotonin; marble burying; head dipping; screen chewing; SB-269970The 5-HT 7 receptor, one of the most recently discovered receptors for serotonin [12], has been found to modulate behaviors affected by antidepressant drugs. In both the forced swim test and the tail suspension test, inactivation or blockade of the 5-HT 7 receptor lead to antidepressantlike behavior [7,13,35]. Furthermore, inactivation or pharmacological blockade of the 5-HT 7 receptor lead to changes in rapid eye movement sleep that are opposite to those seen in depression [8,13]. In addition, it has been shown that certain antidepressants might exert some of their effects by acting directly at the 5-HT 7 receptor [26].Obsessive-compulsive disorder (OCD) is a debilitating disease with an overall prevalence of close to 1 % [15]. There is strong evidence in support of a significant role for 5-HT in OCD and antidepressant drugs, mainly selective serotonin reuptake inhibitors (SSRIs), are the pharmacological treatment of choice for OCD [4,15]. However, as many as 40 % of patients do not respond to currently available treatment options [15], so continued research is necessary. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the c...

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“…Finally, antagonism of 5-HT7-R, via systemic SB-258719 or SB-269970 treatment, also produces antidepressant-like effects, and there is preliminary evidence that this receptor is upregulated by stress (Guscott et al, 2005;Hedlund et al, 2005;Wesolowska et al, 2006;Yau et al, 2001). Along similar lines, Htr7 knockout gene knockout produces an antidepressant-like (and in some studies anxiolytic-like) phenotype and decreased paradoxical sleep (Guscott et al, 2005;Hedlund et al, 2005;Hedlund and Sutcliffe, 2007).…”

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“…Mice lacking the 5-HT 7 receptor were further found to be more prone to induced seizures, suggesting the receptor's implication in epilepsy (Bourson et al 1997;Witkin et al 2007). Clinical studies have suggested 5-HT 7 receptor's antagonists to act as a treatment option in depression and mood disorders (Mnie-Filali et al 2011), OCD (Hedlund and Sutcliffe 2007) as well as anxiety disorders (Wesolowska et al 2006). The receptor has also been linked to migraine (Wang et al 2010b), pain (Leopoldo et al 2011) and irritable bowel syndrome (Zou et al 2007).…”

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“…This disorder has been proven very difficult to model in laboratory animals, which is demonstrated by the large number of models tried out [66]. Marble burying is one of the more well-established models for OCD; however, as anxiolytic agents, such as diazepam and buspirone, have been shown to reduce burying behavior, some investigators consider this more as a model for anxiety [131,132].…”

“…2 Hypothetical model of the induction of hypothermia by an antagonistic 5-HT7R/5-HT1AR-heterodimer. 5-HT-induced hypothermia is mediated by the 5-HT7 receptor at low 5-HT levels, while higher levels of 5-HT also activate the 5-HT1A receptor, which also induces hypothermia and allosterically inhibits 5-HT7 receptor activity burying [66]. Thus, antagonism at the 5-HT7 receptor might also be a valuable approach for the treatment of OCD.…”