Abstract: 5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT₃R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na⁺, K⁺, and Ca²⁺ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT₃R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT₃Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT₃Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ‍-aminobutyric acid (GABA) “disinhibition” mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT₃R-induced GABA “disinhibition” mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT₂R-mediated regulation of anxiety reactions are also activated by 5-HT₃R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT₃Rs. However, given the circuit specific modulation of 5-HT₃Rs on emotion, systemic use of 5-HT₃R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT₃R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.

Key words: 5-Hydroxytryptamine type 3 receptor (5-HT₃R); Anxiety; Medial prefrontal cortex; Amygdala; Hippocampus; Periaqueductal gray

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