5HT1A

5-HT1A, or 5-HT1A receptor, is a subtype of serotonin receptor belonging to the 5-HT1 family. It is a G protein-coupled receptor that primarily couples to Gi/o proteins to inhibit adenylyl cyclase activity, reduce cAMP production, and activate G protein–gated inwardly rectifying potassium (GIRK) channels, leading to neuronal hyperpolarization. The receptor exists both as a somatodendritic autoreceptor on serotonin-producing neurons in the raphe nuclei and as a postsynaptic receptor in several limbic and cortical regions.

Presynaptically, 5-HT1A autoreceptors regulate serotonin release and neuronal firing, providing a brake on serotonergic activity. Postsynaptically, receptor activation modulates neuronal excitability in the hippocampus, amygdala, prefrontal cortex, and other areas involved in mood, anxiety, memory, and fear processing. Through these actions, 5-HT1A receptors contribute to the effects of antidepressants and anxiolytics and influence individual stress responses.

Pharmacology and ligands: Serotonin is the endogenous ligand for 5-HT1A receptors. Clinically relevant agents include buspirone, a partial agonist used for generalized anxiety disorder, and vilazodone, which combines SSRI activity with partial 5-HT1A agonism. 8-OH-DPAT is a common research full agonist, while WAY-100635 is a selective antagonist used to study receptor function. In many antidepressant treatments, autoreceptors desensitize over time, contributing to increased serotonin release and mood improvement.

Genetics and clinical relevance: The HTR1A gene encodes the 5-HT1A receptor. Polymorphisms, such as the promoter variant C(-1019)G, can influence autoreceptor versus postsynaptic expression and have been associated with vulnerability or resilience to anxiety and depressive disorders in some studies. Altered 5-HT1A signaling is also implicated in anxiety disorders, stress response, and the pharmacodynamics of certain antidepressants and anxiolytics.