The tetrameric NMDA receptors are made up of two NR1 subunits and either two NR2 subunits (the NR2 subunits can be further classified into NR2A to NR2D subunits) or two NR3 subunits (NR3A to NR3B, less frequently). While NMDA receptor antagonists are appealing therapeutic candidates for the treatment of resistant depression, they also play significant roles in cognition and learning and are strongly linked to depression. Although the clinical trials supporting the use of NMDA receptor antagonists have yielded mixed results, the reduced function of the receptors still exhibits antidepressant-like action in animal models. A low level of NMDA receptor activity may also prevent the morphological changes in hippocampus neurons brought on by psychological stress, and the expression of NMDA receptors may be suppressed by commercially available antidepressants.
Antagonists of NMDA receptors, like ketamine, quickly alleviated depressive symptoms in both animal models and depressed patients by reducing glutamate activation. However, the usage of ketamine may be restricted due to a number of adverse effects. Memantine, a different non-competitive and low-affinity NMDA receptor antagonist, however, did not start working quickly to provide antidepressant-like effects until a large dose, suggesting a complex mechanism underpinning the pathophysiology of depression. In mice, genetic deletion of the NMDA receptor subunit ε4 (GluRε4, also known as NR2D) can produce effects similar to those of antidepressants. Given that NR2B subunits are primarily found in depression-related brain regions like the hippocampus, specific antagonists of NMDA receptors containing NR2B subunits may make good candidates. However, some results indicate that NR2B and NR2A levels are decreased in the PFC of depressive patients, which is confusing. The NMDA X-ray crystal structure, however, will provide greater insight into the NMDA receptor-based therapy for depression.
The activated APMA receptors increase the expression of BDNF in the hippocampus after interaction with glutamate, which promotes rapid neurogenesis and the sprouting of hippocampal neurons. In numerous animal scenarios, positive allosteric modulators (including piracetam, aniracetam, and cyclothiazide) demonstrate antidepressant profiles similar to tricyclic medications and SSRIs without quickly desensitising AMPA receptors, which is frequently seen with full agonists. Inhibitors of AMPA receptors may reduce the antidepressant-like behaviors generated by ICV administration of lithium in the forced swim and tail suspension paradigms of mice, which may also increase the protein level of glutamate receptor 1 (GluR1) and GluR2 in the mouse hippocampus. There is additional proof that the biological effects of AMPA receptors may be linked to antidepressant medications.
Metabotropic Glutamate Receptors
Our attention has been drawn to metabotropic glutamate receptors (mGluR, class C G-protein-coupled receptors (GPCR)) as a result of negative effects of NMDA receptor antagonists caused by direct reduction of glutamatergic function. Clinical trials for medications that target the mGluR5 receptor to treat depression, anxiety, and fragile X syndrome are now taking place. This receptor is highly expressed in the hippocampus, cortex, striatum, caudate nucleus, and NAc. It is also primarily positioned on postsynaptic membrane. In tail suspension and novelty-suppressed feeding paradigms, antagonists of group II metabotropic glutamate (mGlu2/3) receptor display acute and lasting antidepressant-like effects. mGluR5 antagonists like MTEP may also have antidepressant effects on behaviour. Understanding the pathophysiology of neuropsychiatric illnesses is considerably facilitated by the structure of the mGluR5 transmembrane domain.
Gamma-aminobutyric Acid (GABA)
The neurobiology of major depressive disorder is thought to be influenced by glutamatergic hyperactivity and a glutamate and GABA imbalance. The primary inhibitory transmitter in the central nervous system is GABA, and some brain areas with a direct connection to depression—including the PFC, hippocampus, NAc, amygdala, VTA, and hypothalamus—have GABAergic neuronal projections. Study results have suggested that activating GABA receptors may have antidepressant benefits. The modulators of the α2/α3 GABAA receptor are likely to be new antidepressant prospects. However, the depressive-like behaviors brought on by neuronostatin delivered via ICV can be reversed by the GABA receptor antagonist bicuculline. Our comprehension of depression and the development of possible medications will be furthered by the GABAA receptor's resolved three-dimensional structure.
Drugs used to treat depression, such as tricyclics, selective serotonin re-uptake inhibitors (SSRIs), and serotonin and noradrenaline re-uptake inhibitors, primarily target serotonin and its receptors (SNRIs). Many brain regions associated with depression, including the amygdala, the NAc, and the PFC, are innervated by serotonin from the dorsal raphe (DR), which is located in the periaqueductal grey area, and other raphe nuclei. The antidepressant effect is influenced by elevated serotonin levels. Serotonin activates a number of signalling pathways, including the cAMP-PKA-CREB cascade, by binding to serotonin receptors to produce antidepressant effects. The X-ray structure of the 5-HT3 receptor in association with stabilising nanobodies may aid in our understanding of the molecular mechanisms underlying the antidepressant effects of medications and allow us to rationally develop treatments that are directed at these receptors with fewer adverse effects.