Role of 5-hydroxytryptamine type 3 receptors in the regulation of anxiety reactions

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.

Keywords: 5-Hydroxytryptamine type 3 receptor (5-HT 3 R); Amygdala; Anxiety; Hippocampus; Medial prefrontal cortex; Periaqueductal gray.

Fig. 1. Schematic diagram of main brain regions participating in the regulation of anxiety by 5-hydroxytryptamine (5-HT) type 3 receptors (5-HT₃Rs). The black arrows represent neuronal connections between brain regions. The yellow arrows represent 5-HT projections from the midbrain. mPFC, medial prefrontal cortex; vHIP, ventral hippocampus; PAG, periaqueductal gray; AMYG, amygdala; DRN, dorsal raphe nucleus; MRN, median raphe nucleus.

Fig. 2. Schematic paradigm of the regulation of anxiety by 5-hydroxytryptamine (5-HT) type 3 receptors (5-HT₃Rs) in the amygdala (AMYG). The BLA receives excitatory inputs encoding anxiogenic information from cortical association areas like the mPFC, and then innervates four main excitatory projections: (1) innervates to the CeA inhibitory projecting neurons to induce inhibition of the CeA on downstream brain regions like the PAG and produces anxiogenic effects; (2) innervates to CeA IINs to inhibit BLA excitatory projections innervating CeA inhibitory projecting neurons and produces anxiolytic effects; (3) innervates to ITCs to inhibit CeA IINs and induces "disinhibitory" effects on BLA excitatory projections innervating CeA inhibitory projecting neurons to evoke anxiogenic effects; (4) innervates the vHIP to become involved in the organization of AMYG-vHIP-mPFC neural circuits. 5-HT₃Rs are expressed mainly on the CCK positive IINs in the BLA innervated by 5-HT projections derived from the MRN and DRN, which have high efficiency to induce CCK release, thereby activating CCK-2Rs expressed on BLA excitatory projection fibers innervating ITCs and ITCs themselves, i.e., activating ITCs to promote anxiogenic effects. CeA, central amygdaloid nucleus; BLA, basolateral amygdala; mPFC, medial prefrontal cortex; PAG, periaqueductal gray; vHIP, ventral hippocampus; MRN, median raphe nucleus; DRN, dorsal raphe nucleus; CCK, cholecystokinin; CCK-2R, CCK-2 receptor; ITCs, intercalated cells; IINs, inhibitory interneurons; EP, excitatory projection; IP, inhibitory projection; SP, serotonin (5-HT) projection.

Fig. 3. Schematic paradigm of the regulation of anxiety by 5-hydroxytryptamine (5-HT) type 3 receptors (5-HT₃Rs) in the mFPC. The PL receives excitatory inputs processing anxiogenic information from the vHIP, and then innervates excitatory projecting neurons to the BLA, producing anxiogenic effects. Meanwhile, it also innervates excitatory collaterals to IL inhibitory projections innervating to the CeA inhibitory projecting neurons, to inhibit CeA inhibitory projecting neurons to produce anxiolytic effects. 5-HT₃Rs are densely distributed in both the PL and IL IINs innervated by 5-HT projections derived from the MRN and DRN. Activating 5-HT₃Rs expressed on PL IINs can promote GABA release to inhibit PL excitatory neurons projecting to the BLA, and thereby produces anxiolytic effects. In contrast, activating 5-HT₃Rs expressed on IL IINs will inhibit IL inhibitory neurons projecting to the CeA through the same GABA mechanism, to induce anxiogenic effects. PL, prelimbic cortex; vHIP, ventral hippocampus; BLA, basolateral amygdala; IL, infralimbic cortex; CeA, central amygdaloid nucleus; IINs, intermediate inhibitory neurons; MRN, median raphe nucleus; DRN, dorsal raphe nucleus; GABA, γ‍ -aminobutyric acid; EP, excitatory projection; IP, inhibitory projection; SP, serotonin (5-HT) projection.

Fig. 4. Schematic paradigm of the regulation of anxiety by 5-hydroxytryptamine (5-HT) type 3 receptors (5-HT₃Rs) in the vHIP. The vHIP pyramidal neurons receive excitatory inputs encoding anxiogenic information derived from the BLA, and then send excitatory projections to the PL in the mPFC, thereby becoming involved in the establishment of the AMYG-vHIP-mPFC circuit to promote anxiety reactions. 5-HT₃Rs are expressed on vHIP IINs and presynaptic terminals of 5-HT projections. Activation of 5-HT₃Rs expressed on vHIP IINs can promote GABA release to inhibit pyramidal neurons to produce anxiolytic effects. In contrast, activation of 5-HT₃Rs expressed on presynaptic terminals of 5-HT projections can secondarily promote 5-HT₂Rs expressed on pyramidal neurons, thereby facilitating the AMYG-vHIP-mPFC circuit to promote anxiety. vHIP, ventral hippocampus; BLA, basolateral amygdala; PL, prelimbic cortex; mPFC, medial prefrontal cortex; IINs, intermediate inhibitory neurons; GABA, γ‍ -aminobutyric acid; AMYG, amygdala; Pyr, pyramidal neuron; MRN, median raphe nucleus; DRN, dorsal raphe nucleus; EP, excitatory projection; IP, inhibitory projection; SP, serotonin (5-HT) projection.

Fig. 5. Schematic paradigm of the regulation of anxiety by 5-hydroxytryptamine (5-HT) type 3 receptors (5-HT₃Rs) in the PAG. PAG IINs receive inhibitory inputs from the CeA to relieve tonic inhibition of their downstream excitatory projections, thereby becoming positively involved in anxiety reactions through a "disinhibition" mechanism. 5-HT₃Rs are expressed mainly on presynaptic terminals of 5-HT projections here, and efficiently promote activation of 5-HT₂Rs located in PAG IINs when activated. Activation of 5-HT₂Rs promotes the inhibition of downstream excitatory projections to produce anxiolytic effects. PAG, periaqueductal gray; IINs, intermediate inhibitory neurons; CeA, central amygdaloid nucleus; MRN, median raphe nucleus; DRN, dorsal raphe nucleus; EP, excitatory projection; IP, inhibitory projection; SP, serotonin (5-HT) projection.