More GCs are released into the blood as a result of the psychological stress activating the HPA axis. A significant portion of depressive individuals have larger, more active adrenal glands, elevated cortisol levels in the blood, saliva, and urine, as well as elevated cortisol levels overall. In addition to spine loss, dendritic atrophy, and restriction of neurogenesis in the dentate gyrus of the hippocampus, hypercortisolemia can produce excitotoxicity to pyramidal neurons in the hippocampus. Additionally, redundant GCs might shrink the hippocampus, which would impact the way those parts of the brain that control emotion and reward circuits work. Antidepressant medications could reverse many of these changes. Under typical circumstances, the hippocampus and paraventricular nucleus are both involved in complex feedback loops that the GCs use to aid in the conclusion of the stressful reaction. However, many research studies have shown that depressive patients have dysregulation of GC-mediated feedback loops, including reduced glucocorticoid receptor (GR) function in the HPA axis, peripheral blood mononuclear cells (PBMC), and skin cells.
The hyperactivity of the HPA axis in depression may be explained by anomalies in GR, and GR antagonists (like mifepristone) and GC synthesis inhibitors (like metyrapone) show some therapeutic benefits on depressive symptoms. So, new advanced research is still needed to determine how GCs and GR affect depressed symptoms differently.
Corticotrophin Releasing Factor
There has been a rise in evidence that CRF is a significant factor in depression as seen from recent studies. Patients with depression have higher amounts of CRF, which acts as a neurotransmitter in the bed nucleus (stria terminalis) and the central nucleus (amygdala), as well as more CRF-secreting neurons in the hypothalamus and locus coeruleus. It was also possible to generate depressive behaviors and histonic markers such as hypercortisolemia, anorexia, weight loss, and decreased libido in transgenic mice by infusing CRF into the central nervous system.
CRF binds to its G-protein coupled receptors, CRF1 and CRF2, activating the downstream cAMP signalling as it performs its physiological role. Pituitary and limbic regions, where CRF1 receptors are strongly expressed, influence the activity of the HPA axis. While antagonists of CRF1 receptors could decrease a sequence of depressive behaviours induced by withdrawal from drugs of abuse, inconsistent data still exist. Selective ablation of CRF1 receptors in limbic areas leads to antidepressant-like behaviours in mice subjected to stress. Hepatotoxicity and pharmacokinetic issues with CRF1 receptor antagonists as antidepressants are important sources of frustration.
By acting as auto-receptors on some paraventricular nucleus neurons, CRF2 receptors may have a vital role in maintaining the HPA axis response rather than activating it when stressed (PVN). In a model of persistent mild stress, genetic deletion of the CRF2 receptors causes anxiety-like symptoms in mice, whereas antagonists have calming effects. Some antagonists have even been shown to have antidepressant benefits. Although more research is needed, studying antagonists of CRF2 receptors is of significant interest for treating depression because they have fewer negative effects than antagonists of CRF1 receptors.
When subjected to stress, this neuropeptide, along with CRF, stimulates the release of ACTH from corticotropes situated at the anterior pituitary and thereby adjusts the activity of the HPA axis. It is synthesized in and secreted from paraventricular and supraoptic hypothalamic nuclei. The activated complex exerts its influence across the limbic brain system, particularly in the stria terminalis (bed nucleus) and amygdala, after binding to the GPCRs known as vasopressin V1a and V1b receptors. Vasopressin has a variety of physiological functions, including controlling blood pressure, tension, and anxiety. Vasopressin interacts with its V1b receptors, which are broadly distributed in the limbic brain areas, to have a driving influence on the HPA axis connected to persistent psychological stress. Vasopressin levels were higher in depressive patients, which may have contributed to the hyperactivity of the HPA axis in those patients. SSRI medication treatment can correct this kind of change. More V1b receptor-expressing neurons are present in depressive patients than in healthy individuals. While there are conflicting data about the antidepressant benefits of genetically deleting the V1b receptor gene in mice, antagonists of vasopressin V1b receptors with non-peptide properties have been reported to have an antidepressant effect. More well-designed tests are required to provide a more thorough explanation of these perplexing results.
In order to promote rapid synapses-crossing transmission, glutamate binds to metabotropic glutamate receptors (mGluR) and ionotropic glutamate receptors (iGluR) situated on both neurons and non-neuronal cells. Glutamate is a key excitatory neurotransmitter in the central nervous system. Patients with depression have higher amounts of glutamate (or glutamine) in their brains, cerebrospinal fluid, and plasma. When under stress, presynaptic neurons release glutamate, which then binds to iGluRs (such as NMDA receptors, kainite receptors, and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors on the postsynaptic neurons) and mGluRs (located on both presynaptic and postsynaptic cells) and activates the downstream signaling pathways.