Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine.
Lijia Chang, Kai Zhang, Yaoyu Pu, Y. Qu, Si-Ming Wang, Zhongwei Xiong, Q. Ren, Chao Dong, Yuko Fujita, K. Hashimoto
Pharmacology, Biochemistry and Behavior June 1, 2019 DOI: 10.1016/j.pbb.2019.04.008 via Semantic Scholar
Summary
In a mouse model of chronic social defeat stress, a single intranasal dose of (R)-ketamine produced stronger antidepressant effects than (R,S)-ketamine or (S)-ketamine. Conversely, (S)-ketamine caused the greatest increase in locomotor activity and deficits in prepulse inhibition, followed by (R,S)-ketamine, while (R)-ketamine showed the least. In conditioned place preference tests, repeated intranasal (S)-ketamine and (R,S)-ketamine increased preference scores dose-dependently, indicating abuse liability, whereas (R)-ketamine did not. These findings suggest intranasal (R)-ketamine may be a safer antidepressant option.
Study at a glance
| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Mice |
| Keywords | Medicine |
| Citations | 174 |
| Key finding | Intranasal (R)-ketamine shows greater antidepressant potency and fewer side effects (locomotor activation, prepulse inhibition deficits, and abuse liability) than (R,S)-ketamine or (S)-ketamine in mice. |
Abstract
The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with depression although intranasal use of (R,S)-ketamine in ketamine abusers is popular. In March 5, 2019, nasal spray of (S)-ketamine for treatment-resistant depression was approved as a new antidepressant by the US Food Drug Administration. Clinical study of (R)-ketamine is underway. In a chronic social defeat stress (CSDS) model, we compared the antidepressant effects of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine after a single intranasal administration. Furthermore, we also compared the side effects (i.e., locomotion, prepulse inhibition (PPI), abuse liability) of these three compounds in mice. The order of potency of antidepressant effects after a single intranasal administration was (R)-ketamine > (R,S)-ketamine > (S)-ketamine. In contrast, the order of locomotor activity and prepulse inhibition (PPI) deficits after a single intranasal administration was (S)-ketamine > (R,S)-ketamine > (R)-ketamine. In the conditioned place preference (CPP) test, both (S)-ketamine and (R,S)-ketamine increased CPP scores in mice after repeated intranasal administration, in a dose dependent manner. In contrast, (R)-ketamine did not increase CPP scores in mice. These findings suggest that intranasal administration of (R)-ketamine would be a safer antidepressant than (R,S)-ketamine and (S)-ketamine.