Elsevier

Biological Psychiatry

Volume 58, Issue 10, 15 November 2005, Pages 831-837
Biological Psychiatry

Original article
5-HT7 Receptor Inhibition and Inactivation Induce Antidepressantlike Behavior and Sleep Pattern

https://doi.org/10.1016/j.biopsych.2005.05.012Get rights and content

Background

The 5-hydroxytryptamine7 receptor (5-HT7) is implicated in circadian rhythm phase resetting, and 5-HT7 receptor-selective antagonists alter rapid eye movement (REM) sleep parameters in a pattern opposite from those in patients with clinical depression.

Methods

As sleep, circadian rhythm, and mood regulation are related, we examined 5-HT7 receptor knockout mice in two behavioral models of depression. The forced swim and tail suspension tests are highly predictive for antidepressant drug activity.

Results

Unmedicated 5-HT7−/− mice showed decreased immobility in both tests, consistent with an antidepressantlike behavior. The selective 5-HT7 receptor antagonist SB-269970 also decreased immobility. The selective serotonin reuptake inhibitor citalopram, a widely used antidepressant, decreased immobility in both 5-HT7+/+ and 5-HT7−/− mice in the tail suspension test, suggesting that it utilizes an independent mechanism. The 5-HT7−/− mice spent less time in and had less frequent episodes of REM sleep, also consistent with an antidepressantlike state.

Conclusions

The 5-HT7 receptor might have a role in mood disorders and antagonists might have therapeutic value as antidepressants.

Section snippets

Animals

Ten- to 12-week-old male 5-HT7−/− mice and their male 5-HT7+/+ sibling control animals were used. The generation of the 5-HT7−/− mouse strain has been described previously (Hedlund et al 2003). Briefly, the 5-HT7−/− mice were created by targeted disruption within exon II of the 5-HT7 receptor gene, thus inactivating all known splice variants of the receptor protein. The inactivation was done in embryonic stem cells derived from 129Sv mice and breeding was then performed in C57BL/6J mice. The

Forced Swim Test

In the forced swim test, a two-way ANOVA showed significant effect for genotype [F(1,62) = 8.52, p < .01], treatment (SB-269970 or citalopram) [F(2,62) = 4.85, p < .05], and an interaction between the two [F(2,62) = 8.05, p < .001]. Thus, 5-HT7−/− mice showed decreased immobility compared with 5-HT7+/+ mice (Figure 1A). Animals that had been given a vehicle injection showed slightly less immobility than untreated animals. The selective 5-HT7 receptor antagonist SB-269970 induced decreased

Discussion

There are two major findings in the present study. First, unmedicated 5-HT7−/− mice showed reduced immobility in both the forced swim and the tail suspension tests. These tests are widely used as predictors of antidepressant effect of a drug and to evaluate strain differences in animals. Hence, the 5-HT7−/− mice show an antidepressantlike behavior. Second, 5-HT7−/− mice showed an altered sleep pattern, spending less time in REM. Sleep disturbances observed in depression often include decreased

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