An integrative view on the cell-type-specific mechanisms of ketamine's antidepressant actions.

Ketamine induces a complex cascade of effects on diverse groups of brain cells through several receptors. In the cortex and hippocampus, the concomitant inhibition of interneurons and activation of excitatory neurons is triggered by rapid pharmacological effects and the subsequent engagement of signaling pathways that activate protein synthesis. The lasting effects of ketamine are sustained by the activation of neuronal plasticity mechanisms, including control of excitability and synaptogenesis in the cortex and hippocampus. Correlative evidence suggests the contribution of oligodendrocytes, astroglia, and microglia to the antidepressant effects of ketamine, but the casual involvement of these cell types has not been definitively tested. Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl- d -aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine. Over the past six decades, the use of ketamine has evolved from an anesthetic and recreational drug to the first non-monoaminergic antidepressant approved for treatment-resistant major depressive disorder (MDD). Subanesthetic doses of ketamine and its enantiomer (S)-ketamine (esketamine) directly bind to several neurotransmitter receptors [including N-methyl-d-aspartic acid receptor (NMDAR), κ and μ opioid receptor (KOR and MOR)] widely distributed in the brain and across different cell types, implicating several potential molecular mechanisms underlying the action of ketamine as an antidepressant. This review examines preclinical studies investigating cell-type-specific mechanisms underlying the effects of ketamine on behavior and synapses. Cell-type-specific approaches are crucial for disentangling the critical mechanisms involved in the therapeutic effect of ketamine. [ABSTRACT FROM AUTHOR]