The 5-HT7 receptor has been postulated to play a role in depression based partly on its distribution in the brain and also on the observation that chronic treatment with antidepressants results in downregulation of this receptor. Additional support for this hypothesis has been gained by a recent study showing that 5-HT7 receptor knockout mice demonstrate antidepressant-like profiles in forced swim and tail suspension tests . The identification of selective antagonist tool compounds has helped add further evidence in support of the hypothesis. For example, SB-269970, 16, exhibits antidepressant-like activity, even though this compound has a rather poor PK profile. SB-656104-A, 17, has been identified as a 5-HT7 antagonist with better PK properties and has been shown to modulate REM sleep in rats in a manner consistent with potential antidepressant-like activity .
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