ABSTRACT
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.
Subject(s)
Indoles/pharmacology , Phenols/pharmacology , Psychotropic Drugs/pharmacology , Pyridines/pharmacology , Receptors, Serotonin , Serotonin Antagonists/pharmacology , Sulfonamides/pharmacology , Animals , Anxiety Disorders/drug therapy , Anxiety Disorders/metabolism , Body Temperature/drug effects , Cyclic GMP/metabolism , Depressive Disorder/drug therapy , Depressive Disorder/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Hypothermia/chemically induced , Indoles/chemistry , Male , Mice, Inbred C57BL , Mice, Inbred ICR , Mice, Knockout , Motor Activity/drug effects , Motor Activity/physiology , Phenols/chemistry , Psychotropic Drugs/chemistry , Pyridines/chemistry , Receptors, Serotonin/genetics , Receptors, Serotonin/metabolism , Schizophrenia/drug therapy , Schizophrenia/metabolism , Serotonin Antagonists/chemistry , Sulfonamides/chemistryABSTRACT
The 5-HT7 receptor is the most recently identified receptor subtype within a family of 5-HT receptors activated by the neurotransmitter serotonin. There has been significant interest in investigating the potential role of this receptor in psychiatric disorders including depression, anxiety, and schizophrenia. Behaviors of 5-HT7 +/+ (wild-type or WT) and 5-HT7 -/- (receptor knockout or KO) mice were compared across 10 different assays (7 for anxiety, 1 for depression, 2 for psychosis) to identify differences that could indicate clinical potential for 5-HT7 receptor antagonism. Evaluation of KO vs. WT mice demonstrated significant differences between the genotypes in the fear conditioning, shock-probe burying, novelty-suppressed feeding, punishment memory, forced swim test, and d-amphetamine hyperactivity assays. There was not consistency in either the direction of behavioral effects across genotypes or across assays. Thus, data from these behavioral assays did not uniformly support the idea that 5-HT7 receptors constitute an important drug target for these psychiatric disorders. The present findings are generally congruent with the mixed results in the literature on the behaviors of 5-HT7 -/-mice and with the data on effects of 5-HT7 receptor antagonists in rodent models that detect activity of anxiolytic, antidepressant, and antipsychotic effects.
