Fig. 3: Ketamine modulates cellular metabolism and promotes adenosine efflux via ENT1/2.
From: Adenosine signalling drives antidepressant actions of ketamine and ECT
a, Schematic of intracellular adenosine generation and its efflux through ENT1/2. b,c, Inhibition of ENT1/2 blocks ketamine-induced adenosine release. b, Time course of extracellular adenosine in the mPFC after ketamine administration with or without pretreatment with the ENT1/2 inhibitor dipyridamole (1 µg, intracerebroventricular injection). c, Quantification of peak adenosine and AUC (normalized to vehicle). d, Ketamine decreases the intracellular ATP/ADP ratio in mPFC excitatory neurons. Left, representative image of PercevalHR expression in CaMKII+ neurons. Scale bar, 200 µm. Middle, time course of the ATP/ADP ratio after ketamine (10 mg kg−1, i.p. injection) or saline treatment. Right, corresponding AUC (normalized to saline). e,f, Intracellular ATP/ADP ratios in mPFC GABAergic neurons (e) and astrocytes (f). Panels show representative images, time courses and saline-normalized AUCs as in d. g, Experimental workflow for mitochondrial isolation and subsequent metabolic flux analyses in the mouse prefrontal cortex. h, PCA of the metabolomic profiles, illustrating separation of the treatment groups along the first two principal components. Ellipses represent 95% confidence intervals calculated using the multivariate t-distribution. Data are the mean ± s.e.m. (shading in b, d–f; error bars in c–f). Statistics: two-tailed paired t-test (c) or two-tailed unpaired t-tests (d–f). **P < 0.01, ***P < 0.001. See Supplementary Table 1 for detailed statistics. The schematics in a and g were created using BioRender (https://www.biorender.com).
