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. 2014 Jul;20(7):582-90.
doi: 10.1111/cns.12247.

Interplay Between Serotonin 5-HT1A and 5-HT7 Receptors in Depressive Disorders

Free PMC article

Interplay Between Serotonin 5-HT1A and 5-HT7 Receptors in Depressive Disorders

Vladimir S Naumenko et al. CNS Neurosci Ther. .
Free PMC article


Serotonin (5-hydroxytryptamine or 5-HT) is an important neurotransmitter regulating a wide range of physiological and pathological functions via activation of heterogeneously expressed 5-HT receptors. Besides the important role of 5-HT receptors in the pathogenesis of depressive disorders and in their clinical medications, underlying mechanisms are far from being completely understood. This review focuses on possible cross talk between two serotonin receptors, 5-HT1A and the 5-HT7 . Although these receptors are highly co-expressed in brain regions implicated in depression, and most agonists developed for the 5-HT1A or 5-HT7 receptors have cross-reactivity, their functional interaction has not been yet established. It has been recently shown that 5-HT1A and 5-HT7 receptors form homo- and heterodimers both in vitro and in vivo. From the functional point of view, heterodimerization has been shown to play an important role in regulation of receptor-mediated signaling and internalization, suggesting the implication of heterodimerization in the development and maintenance of depression. Interaction between these receptors is also of clinical interest, because both receptors represent an important pharmacological target for the treatment of depression and anxiety.

Keywords: 5-HT1A/5-HT7 receptor cross talk; Depression; G protein-coupled receptor (GPCR); Receptor dimerization; Serotonin.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Hypothetical model explaining the functional role of 5‐HT 1A‐5‐HT 7 heterodimerization. Under physiological conditions (left), the amount of 5‐HT 1A‐5‐HT 7 heterodimers in presynaptic 5‐HT neurons is higher than in postsynaptic neurons, representing a mechanism responsible for the differential 5‐HT or SSRI‐mediated internalization obtained for the 5‐HT 1A auto‐ versus heteroreceptors. By depression (right), the relationship between 5‐HT 1A‐5‐HT 1A homodimers and 5‐HT 1A‐5‐HT 7 heterodimers in presynaptic 5‐HT neurons becomes shifted toward 5‐HT 1A‐5‐HT 1A homodimers. This will result in decreased 5‐HT or SSRI‐mediated internalization of 5‐HT 1A autoreceptors, which in turn will lead to 5‐HT 1A receptor‐mediated inhibition of 5‐HT release. On the postsynaptic neurons, higher amount of heterodimers ([5‐HT 1A‐5‐HT 7] > [5‐HT 1A‐5‐HT 1A]) is expected during depression. Consequently, internalization of postsynaptic 5‐HT 1A receptors will be increased, leading to the increased neuronal excitability.

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