(R,S)‐ketamine exerts robust antidepressant effects in patients with depression when given at sub‐anesthetic doses. Each of the enantiomers in this racemic mixture, (R)‐ketamine and (S)‐ketamine, have been reported to exert antidepressant effects individually. However, the neuropharmacological effects of these enantiomers and the mechanisms underlying their antidepressive actions have not yet been fully elucidated. Therefore, we investigated the effect of (R,S)‐, (R)‐, and (S)‐ketamine on brain activity by functional MRI (fMRI) in conscious rats and compared these with that of N‐methyl‐D‐aspartate receptor (NMDAR) antagonist MK‐801 (n = 5~7). We also assessed their pharmacokinetic profiles (n = 4) and their behavioral effects (n = 7~9). This pharmacological MRI study revealed a significant positive response to (S)‐ketamine specifically in the cortex, nucleus accumbens and striatum. In contrast, negative fMRI responses were observed in various brain regions after (R)‐ketamine administration. (R,S)‐ketamine, evoked significant positive fMRI responses specifically in the cortex, nucleus accumbens and striatum, and this fMRI response pattern was comparable with that of (S)‐ketamine. MK‐801‐induced similar fMRI response pattern to (S)‐ketamine. The fMRI responses to (S)‐ketamine and MK‐801 showed differential temporal profiles, which corresponded with brain concentration profiles. (S)‐ketamine and MK‐801 significantly increased locomotor activity, while (R)‐ketamine produced no noticeable change. (R,S)‐ketamine tended to increase locomotor activity. Our novel fMRI findings show that (R)‐ketamine and (S)‐ketamine induce completely different fMRI response patterns on rat, and that the response produced by the latter is similar to that elicited by an NMDAR antagonist. Our findings provide insight into the antidepressant mechanism of (R,S)‐ketamine.
The utility of noninvasive DCE-MRI with Gd-EOB-DTPA as a tool for the assessment of Mrp2-deficient hyperbilirubinuria rats was demonstrated. We also clarified that the lower vascular density in the EHBRs may cause delayed uptake of the contrast agent compared with the control rats. In addition, the lower Mrp2 transporter expression may cause the lower efflux of the contrast agent from the Mrp2-deficient rats compared with the control rats.
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