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Molecular and cellular dissection of NMDA receptor subtypes as antidepressant targets
Journal
Neuroscience and biobehavioral reviews
Volume
84
Pages / Article-Number
352-358
Mesh terms
Animals; Antidepressive Agents, therapeutic use; Depressive Disorder, Major, drug therapy; Excitatory Amino Acid Antagonists, therapeutic use; Humans; Molecular Targeted Therapy, methods; Protein Isoforms, drug effects
Abstract
A growing body of evidence supports the idea that drugs targeting the glutamate system may represent a valuable therapeutic alternative in major depressive disorders (MDD). The rapid and prolonged mood elevating effect of the NMDA receptor (NMDAR) antagonist ketamine has been studied intensely. However, its clinical use is hampered by deleterious side-effects, such as psychosis. Therefore, a better understanding of the mechanisms of the psychotropic effects after NMDAR blockade is necessary to develop glutamatergic antidepressants with improved therapeutic profile. Here we review recent experimental data that addressed molecular/cellular determinants of the antidepressant effect mediated by inactivating NMDAR subtypes. We refer to results obtained both in pharmacological and genetic animal models, ranging from global to conditional NMDAR manipulation. Our main focus is on the contribution of different NMDAR subtypes to the psychoactive effects induced by NMDAR ablation/blockade. We review data analyzing the effect of NMDAR subtype deletions limited to specific neuronal populations/brain areas in the regulation of mood. Altogether, these studies suggest effective and putative specific NMDAR drug targets for MDD treatment.
