Serotonin receptors in depression and anxiety: insights from animal studies

The takeaway

Almost every serotonin receptor subtype plays a role in regulating mood and anxiety. Animal research shows that activating or blocking different receptors can produce antidepressant- or anxiolytic-like effects, providing multiple targets beyond the serotonin transporter for future treatments.

The science

Animal studies show that nearly all serotonin receptor families (5-HT₁ to 5-HT₇) are involved in mood and anxiety regulation:
- 5-HT_1A: Postsynaptic activation produces antidepressant-like effects, while presynaptic blockade may accelerate SSRI efficacy; autoreceptor desensitization is key to treatment onset. Activation of these receptors also generally reduces anxiety-like behaviors, as seen with buspirone.
- 5-HT_1B: Postsynaptic stimulation or presynaptic blockade can enhance antidepressant response and modulate anxiety, though results are mixed.
- 5-HT_2A: Blockade reduces depressive- and anxiety-like behaviors and may augment SSRIs, especially in resistant depression.
- 5-HT_2B/2C: 5-HT_2B stimulation supports SSRI responses but carries cardiovascular risks; 5-HT_2C shows complex bidirectional effects, with both agonists and antagonists showing antidepressant- and anxiolytic-like actions.
- 5-HT₃: Antagonists consistently produce antidepressant- and anxiolytic-like effects and may underlie vortioxetine’s cognitive benefits and faster onset.
- 5-HT₄: Agonists enhance neurogenesis and yield rapid antidepressant-like responses; their role in anxiety remains less clear.
- 5-HT_5A, 5-HT₆, 5-HT₇: Still poorly defined, but antagonists at 5-HT_5A, mixed effects at 5-HT₆, and blockade of 5-HT₇ show antidepressant- and anxiolytic-like activity in rodents.Notably, multimodal drugs that act on several serotonin receptors simultaneously are in development, with early candidates showing robust antidepressant- and anxiolytic-like effects in animal models.

Why it matters

SSRIs are often slow and may not fully relieve symptoms, leaving many patients affected. Understanding serotonin receptor subtypes could lead to faster, more effective treatments that also enhance cognition in depression and anxiety. This insight deepens our understanding of serotonin’s role in mood control.

Orginal article

https://doi.org/10.1016/j.lfs.2018.08.050