Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_205_библиотеки_им_акад_М_И_Перельмана

ketamine that are primarily channel-blocking agents that interfere with the receptor’s ion channel. These drugs can bind to selectively expressed subunits of the NMDA receptor or to sites common to all NMDA receptors. The second class contains drugs that are reported to act by modulating the binding or function of the glycine co-agonist site on the NMDA receptor. To varying degrees these drugs can indirectly modulate the ion transport through the receptor. These drugs are believed to produce their antidepressant effects by promoting enhanced presynaptic glutamate release and/or limiting neuronal toxicity. 2. Drugs targeting metabotropic glutamate receptors 2 and 3 (mGluR2/3): mGluR2/3 activation serves to inhibit glutamate release and serves as a target to modulate glutamate release. On the basis of the proposed pathophysiological model presented above, arguments can be made for both inhibiting tonic glutamate release and transiently stimulating glutamate release, such as is believed to happen with ketamine treatment. Both positive and negative allosteric modulators of mGluR2/3 are being studied as treatment for mood disorders. 3. Drugs stimulating hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation: These drugs can act either as more direct agonists of glutamate or as modulators of receptor function. To date there is preclinical evidence suggesting that drugs in this class possess antidepressant properties, but clinical confirmation is required. 4. Drugs targeting intracellular mechanisms: Because preclinical evidence suggests that activation of the mechanistic (mammalian) target of the rapamycin complex 1 (mTORC1) pathway is critical to the mechanism of ketamine’s action, there have been attempts to develop drugs that can more directly modulate the pathway downstream of the glutamatergic receptors. 5. Drugs facilitating glutamate uptake: On the basis of evidence suggesting that glial cell abnormalities and impaired glutamate uptake are associated with the pathogenesis and pathophysiology of mood disorders, there have been attempts to identify and utilize drugs that can facilitate glutamate clearance in efforts to treat mood disorders. Rodent studies support this approach; however, the clinical studies for one potential agent, riluzole, have yielded inconsistent results at best. These equivocal findings may suggest that drugs that modulate glutamate uptake could have benefits prophylactically but may not be highly effective in treatment.