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Serotonin receptors 5-HT_1A and 5-HT₇ are highly coexpressed in brain regions implicated in depression. However, their functional interaction has not been established. In the present study we show that 5-HT_1A and 5-HT₇ receptors form heterodimers both in vitro and in vivo. Foerster resonance energy transfer-based assays revealed that, in addition to heterodimers, homodimers composed either of 5-HT_1A or 5-HT₇ receptors together with monomers coexist in cells. The highest affinity for complex formation was obtained for the 5-HT₇–5-HT₇ homodimers, followed by the 5-HT₇–5-HT_1A heterodimers and 5-HT_1A–5-HT_1A homodimers. Functionally, heterodimerization decreases 5-HT_1A-receptor-mediated activation of G_i protein without affecting 5-HT₇-receptor-mediated signalling. Moreover, heterodimerization markedly decreases the ability of the 5-HT_1A receptor to activate G-protein-gated inwardly rectifying …