Effects of 5-HT7 receptor antagonists on behaviors of mice that detect drugs used in the treatment of anxiety, depression, or schizophrenia

• Published in: Behavioural brain research 2019-02, Vol.359, p.467-473
• Main Authors: Maxwell, Julia, Gleason, Scott D., Falcone, Julie, Svensson, Kjell, Balcer, Olivia M., Li, Xia, Witkin, Jeffrey M.
• Format: Article
• Language: English
• Subjects: 5-HT7 receptors; Anxiety; Depression; DR-4004; SB-269970; Schizophrenia
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2018.11.019

5-HT7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT7 receptors in the brain in vivo. 5-HT produced hypothermia in wildtype mice by either i.p. or i.c.v. routes but did not in 5-HT7 receptor knockout mice. 5-HT-induced hypothermia was not attenuated by drugs selectively blocking alpha1 or 5-HT1A receptors. Doses of DR-4004 and SB-269970 that blocked 5-HT-induced hypothermia, did not display significant anxiolytic-like (elevated plus maze; vogel conflict) or antidepressant-like efficacy (tail-suspension test) in mouse models. These compounds did demonstrate some antipsychotic-like properties in the PCP-induced hyperactivity assay and anxiolytic/anti-stress effects in the stress-induced cGMP assay. Negative findings were substantiated by positive control drugs that were active in each assay system. We conclude that 5-HT-induced hypothermia can be used to estimate blockade of central 5-HT7 receptors. Effects of DR-4004 and SB-269970 in animal models are generally consistent with the experimental literature that the evidence is mixed or not robust regarding the potential efficacy of 5-HT7 receptor antagonism in the treatment of anxiety, depression, or schizophrenia.