PMID- 31397936
OWN - NLM
STAT- MEDLINE
DCOM- 20200428
LR  - 20200428
IS  - 1098-2396 (Electronic)
IS  - 0887-4476 (Linking)
VI  - 73
IP  - 12
DP  - 2019 Dec
TI  - (R)- and (S)-ketamine induce differential fMRI responses in conscious rats.
PG  - e22126
LID - 10.1002/syn.22126 [doi]
AB  - (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.
CI  - (c) 2019 Wiley Periodicals, Inc.
FAU - Masaki, Yukiko
AU  - Masaki Y
AUID- ORCID: 0000-0001-6386-3602
AD  - Imaging Biomarker, Biomarker R&D Department, Shionogi & Co., Ltd., Osaka, Japan.
FAU - Kashiwagi, Yuto
AU  - Kashiwagi Y
AD  - Imaging Biomarker, Biomarker R&D Department, Shionogi & Co., Ltd., Osaka, Japan.
FAU - Watabe, Hiroshi
AU  - Watabe H
AD  - Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan.
FAU - Abe, Kohji
AU  - Abe K
AD  - Imaging Biomarker, Biomarker R&D Department, Shionogi & Co., Ltd., Osaka, Japan.
LA  - eng
PT  - Journal Article
DEP - 20190905
PL  - United States
TA  - Synapse
JT  - Synapse (New York, N.Y.)
JID - 8806914
RN  - 0 (Antidepressive Agents)
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 690G0D6V8H (Ketamine)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
SB  - IM
MH  - Animals
MH  - Antidepressive Agents/pharmacology
MH  - Brain/diagnostic imaging/*drug effects
MH  - Dizocilpine Maleate/pharmacology
MH  - Excitatory Amino Acid Antagonists/*pharmacology
MH  - Ketamine/*pharmacology
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Motor Activity/drug effects
MH  - Rats
MH  - Rats, Wistar
OTO - NOTNLM
OT  - NMDAR
OT  - depression
OT  - ketamine
OT  - pharmacological MRI
EDAT- 2019/08/10 06:00
MHDA- 2020/04/29 06:00
CRDT- 2019/08/10 06:00
PHST- 2018/12/26 00:00 [received]
PHST- 2019/07/24 00:00 [revised]
PHST- 2019/08/05 00:00 [accepted]
PHST- 2019/08/10 06:00 [pubmed]
PHST- 2020/04/29 06:00 [medline]
PHST- 2019/08/10 06:00 [entrez]
AID - 10.1002/syn.22126 [doi]
PST - ppublish
SO  - Synapse. 2019 Dec;73(12):e22126. doi: 10.1002/syn.22126. Epub 2019 Sep 5.