Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine in a chronic social defeat stress model

• Published in: Psychopharmacology Vol. 235; no. 11; pp. 3177 - 3185
• Main Authors: Zhang, Kai, Toki, Hidetoh, Fujita, Yuko, Ma, Min, Chang, Lijia, Qu, Youge, Harada, Shingo, Nemoto, Tetsuhiro, Mizuno-Yasuhira, Akiko, Yamaguchi, Jun-ichi, Chaki, Shigeyuki, Hashimoto, Kenji
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-11-2018; Springer; Springer Nature B.V
• Subjects: Analysis; Animals; Antidepressants; Antidepressive Agents - administration & dosage; Antidepressive Agents - chemistry; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Brain; Brain - drug effects; Brain - metabolism; Care and treatment; Chronic Disease; Depression (Mood disorder); Depression - drug therapy; Depression - metabolism; Depression - psychology; Deuterium; Deuterium - administration & dosage; Deuterium - chemistry; Deuterium - metabolism; Disease Models, Animal; Dosage and administration; Glutamic acid receptors; Isotope effect; Isotopes; Ketamine; Ketamine - administration & dosage; Ketamine - analogs & derivatives; Ketamine - chemistry; Ketamine - metabolism; Male; Mental depression; Metabolism; Mice; Mice, Inbred C57BL; N-Methyl-D-aspartic acid receptors; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry; Social interactions; Stress, Psychological - drug therapy; Stress, Psychological - metabolism; Stress, Psychological - psychology; Treatment Outcome; 2; Deuterium isotope effect; ketamine; 6; (; hydroxynorketamine; Metabolism; (2R,6R)-hydroxynorketamine; (R)-ketamine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-018-5017-2

Rationale
(
R,S
)-ketamine, an
N
-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (
R,S
)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (
R,S
)-ketamine, the deuterium isotope effects in the antidepressant actions of (
R
)-ketamine, which is more potent than (
S
)-ketamine, are unknown.
Methods
We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (
R
)-ketamine in a chronic social defeat stress (CSDS) model.
Results
Pharmacokinetic studies showed that levels of (2
R
,6
R
)-d
1
-hydroxynorketamine [(2
R
,6
R
)-d
1
-HNK], a final metabolite of (
R
)-d
2
-ketamine, in the plasma and brain after administration of (
R
)-d
2
-ketamine (10 mg/kg) were lower than those of (2
R
,6
R
)-HNK from (
R
)-ketamine (10 mg/kg), indicating deuterium isotope effects in the production of (2
R
,6
R
)-HNK. In contrast, levels of (
R
)-ketamine and its metabolite (
R
)-norketamine in the plasma and brain were the same for both compounds. In a CSDS model, both (
R
)-ketamine (10 mg/kg) and (
R
)-d
2
-ketamine (10 mg/kg) showed rapid and long-lasting (7 days) antidepressant effects, indicating no deuterium isotope effect in the antidepressant effects of (
R
)-ketamine.
Conclusions
The present study suggests that deuterium substitution of hydrogen at the C6 position slows the metabolism from (
R
)-ketamine to (2
R
,6
R
)-HNK in mice. In contrast, we did not find the deuterium isotope effects in terms of the rapid and long-lasting antidepressant effects of (
R
)-ketamine in a CSDS model. Therefore, it is unlikely that (2
R
,6
R
)-HNK is essential for antidepressant effects of (
R
)-ketamine.