Figure 3.

Anxiolytic mechanism of tandospirone. 5-HT_1A: (a) Biological factors have been implicated in the pathogenesis of anxiety. Neurochemical evidence suggests that the dysregulation of serotonin, norepinephrine, gamma-aminobutyric acid (GABA), glutamate, and peptides (corticotropin releasing factor, cholecystokinin, neuropeptide Y) transmission systems are strongly correlated with the pathophysiology of anxiety. In the classic concept of stress, homeostasis is threatened by physical and psychological events, known as stressors. Behavior is aimed at assessing the destabilizing potential of the stressor. If the stressor event does not correspond to any cognitive representation based on previous subjective experiences, there is an increase in alertness, hypervigilance, focused attention, and cognitive processing. The interface between sensory information received and the evaluation process is formed in the limbic region of the brain, which comprises structures such as the hippocampus, the amygdala, and the medial prefrontal cortex (mPFC). The components of the human fear circuit, which can be of particular relevance for destabilization produced by the stressor and, consequently, induction of anxiety, include mPFC (subservient fear extinction processes), the amygdala (risk assessment processing), and the hippocampus. The ascending serotonergic pathway that projects from the DRN into the hippocampus may be implicated in the genesis of behavioral inhibition observed in dangerous situations. During episodes of anxiety crisis, it is postulated that these serotonergic inputs in the hippocampus activate 5-HT_1A receptors in GABAergic interneurons. In this case, 5-HT_1A receptors coupled to the Gαi/0 protein block adenylate cyclase (AC), prevent the formation of cyclic adenosine monophosphate (cAMP) and reduce the activation of protein kinase A (PKA) which, once reduced, decrease the permeability of calcium (Ca²⁺) to specific channels located in the cell membrane. This reduction in the calcium influx into the GABAergic interneuron culminates in the blocking the exocytosis of the GABA neurotransmitter. The reduction of the hippocampal GABAergic transmission causes an increase in the number of post-synaptic pyramidal glutamatergic neurons fires, stimulating anxiety-related regions such as the amygdala and the DRN, which feeds back and over-stimulates the anxiety-related circuit; (b,c); tandospirone has a promising anxiolytic effect, which has been shown in animal models, especially of the generalized anxiety disorder (GAD). Tandospirone acts as an anxiolytic by activating the post-synaptic 5-HT_1A receptor coupled to the Gαi/0protein, resulting in reduced cAMP formation and PKA inhibition. On the other hand, it activates the G protein-controlled internal rectifying potassium channels (GIRK) by releasing Gβγ subunits, leading to intracellular potassium (K⁺) efflux, hyperpolarization of target neurons and, finally, inhibition of the local neuronal activity [24]; (d) another mechanism by which tandospirone exerts its anxiolytic effect is by increasing the release of dopamine (DA) in the VTA. In this case, tandospirone activates the 5-HT_1A receptor in DRN or mPFC, directly or indirectly, stimulating dopaminergic transmission in VTA [24].