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Ketamine’s Antidepressant Actions: Potential Mechanisms in the Primate Medial Prefrontal Circuits That Represent Aversive Experience

      There is increasing interest in the mechanisms underlying the rapid antidepressant actions of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine (
      • Krystal J.H.
      • Sanacora G.
      • Duman R.S.
      Rapid-acting glutamatergic antidepressants: The path to ketamine and beyond.
      ). In contrast to classical antidepressant treatments where efficacy builds over weeks, ketamine’s actions can be seen within hours after intravenous administration, or even within minutes following intranasal administration (
      • Opler L.A.
      • Opler M.G.
      • Arnsten A.F.T.
      Ameliorating treatment-refractory depression with intranasal ketamine: Potential NMDA receptor actions in the pain circuitry representing mental anguish.
      ), and can last for several days after a single administration. In their functional magnetic resonance imaging study of anesthetized monkeys, Lv et al. (
      • Lv Q.
      • Yang L.
      • Li G.
      • Wang Z.
      • Shen Z.
      • Yu W.
      • et al.
      Large-scale persistent network reconfiguration induced by ketamine in anesthetized monkeys: Relevance to mood disorders.
      ) found that intramuscular administration of ketamine 18 hours before the functional magnetic resonance imaging scan reduced the correlations of spontaneous blood oxygen level–dependent (BOLD) signal fluctuations within the medial prefrontal cortex (mPFC) circuits associated with reward, schematically illustrated in Figure 1A in dark blue. This pattern was of particular interest, as mPFC circuits are often dysregulated in patients with major depressive disorder. In particular, depressed patients show overactivation of the ventral mPFC subgenual cortex, Brodmann area (BA) 25 (
      • Mayberg H.S.
      • Lozano A.M.
      • Voon V.
      • McNeely H.E.
      • Seminowicz D.
      • Hamani C.
      • et al.
      Deep brain stimulation for treatment-resistant depression.
      ), while increased activation of the dorsomedial anterior cingulate cortex (BA24) to fearful faces correlates with subsequent ketamine antidepressant response [reviewed in (
      • Opler L.A.
      • Opler M.G.
      • Arnsten A.F.T.
      Ameliorating treatment-refractory depression with intranasal ketamine: Potential NMDA receptor actions in the pain circuitry representing mental anguish.
      )]. Thus, the finding that ketamine reduced correlated activity in these circuits in monkeys suggests it may normalize brain activity in patients with depression.
      Figure thumbnail gr1
      Figure 1(A) Schematic illustration of the results of Lv et al. (
      • Lv Q.
      • Yang L.
      • Li G.
      • Wang Z.
      • Shen Z.
      • Yu W.
      • et al.
      Large-scale persistent network reconfiguration induced by ketamine in anesthetized monkeys: Relevance to mood disorders.
      ) showing reduced functional connectivity (dark blue) in monkey medial prefrontal cortex (PFC) and subcortical structures 18 hours following ketamine. Anatomical pathways mediating the emotional aspects of pain are shown in red, with Brodmann area (BA) 24, dorsomedial PFC (dmPFC), and BA25 outlined; the dorsolateral PFC (dlPFC) (not shown, as it is on the lateral surface) connects to BA25 via rostral medial PFC. (B) Effects of N-methyl-D-aspartate (NMDA) receptor blockade on dlPFC delay cell firing, where iontophoresis of an NMDA receptor-NR2B antagonist causes complete loss of the representation of visual space. (C) Time course of neural signals related to gains and losses in dmPFC, dlPFC, and the anterior cingulate cortex (BA24). Shown are the fractions of neurons with significant gain- or loss-related activity within each region at different time lags from the time of target or feedback onset. Caud, caudate; Thal, thalamus; VS, ventral striatum. [(B) Adapted from Wang et al. (
      • Wang M.
      • Yang Y.
      • Wang C.J.
      • Gamo N.J.
      • Jin L.E.
      • Mazer J.A.
      • et al.
      NMDA receptors subserve working memory persistent neuronal firing in dorsolateral prefrontal cortex.
      ). (C) Adapted from Seo and Lee (
      • Seo H.
      • Lee D.
      Behavioral and neural changes after gains and losses of conditioned reinforcers.
      )].
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