Tianeptine is neuroprotective via multiple neurochemical and cellular mechanisms. When an organism is under stress, or perceives itself under stress, the hypothalamus secretes corticotropin-releasing hormone/factor (CRH/CRF). CRH/CRF in turn increases secretion of adrenocorticotrophic hormone (ACTH) from the anterior pituitary. ACTH in turn stimulates the release of glucocorticoids from the adrenal cortex. Persistent, uncontrolled physical and psychosocial stress causes excess cortisol secretion from the adrenal glands. Excess cortisol causes dendritic shrinkage in the hippocampus and a contrasting growth of dendrites in the lateral amygdala. These stress-induced changes tend to lower mood; they can cause clinical depression in the genetically vulnerable. Current evidence suggests that tianeptine acts to prevent and even reverse stress-induced neural damage, promoting both neuronal survival and synaptic plasticity. Sustained use of tianeptine tends to "normalise" the hypothalamic-pituitary-adrenal (HPA) system. Tianeptine reduces basal and stress-evoked activity of the HPA, helping its users cope in a stressful environment. Treatment with tianeptine inhibits corticosterone-induced gene transcription. Stress-induced increases in plasma ACTH, and corticosterone levels are diminished. So too is basal activity of corticotropin-releasing factor (CRF) neurons and their sensitivity to stress. Prolonged tianeptine use also reduces some forms of stress-induced apoptosis ("programmed cell-death"), notably in the temporal cortex and dentate gyrus of the hippocampus. At the molecular level, tianeptine exerts profound effects on the glutamate system. The amino acid glutamate serves as the main excitatory neurotransmitter in the brain. Its excitatory action is mediated by via multiple receptor subtypes. The three main subtypes of glutamate-gated ion channel are kainate, ampa, and N-methyl-D-aspartate (NMDA). Tianeptine prevents overstimulation of AMPA/kainate type glutamate receptors in the hippocampus that regulate Ca2+ entry into the nerve cell; excess Ca2+ entry into nerve cells is toxic. Tianeptine also modulates the NMDA glutamate receptors. NMDA receptors for glutamate play a critical role in mediating the functional and intracellular effects of stress. Tianeptine reportedly targets the phosphorylation-state of glutamate receptors in the hippocampus, "normalising" stress-induced changes in the amplitude ratio NMDA glutamate receptor to AMPA/kainate glutamate receptor-mediated excitatory post-synaptic currents.