Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant-like effects of ketamine.
Yong-Yu Yin, Jiao-Zhao Yan, Qian-Qian Wei, Si-Rui Sun, Yu-Qiang Ding, Li-Ming Zhang, Yun-Feng Li
British Journal of Pharmacology December 1, 2024 DOI: 10.1111/bph.17324 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamine PCPA 5 7-DHT NBQX |
| Dose | 10 mg·kg-1, i.p. |
| Duration | 60 min and 24 h post-injection |
| Topics | Ketamine Serotonin Esketamine |
| Keywords | 5‐ht Ampa Antidepressant Sustained Ketamine-assisted therapy Mood disorder therapy Neurotransmitters serotonin Brain chemistry Neurore |
| Citations | 13 |
| Key points | Sustained but not rapid antidepressant-like effects of ketamine require serotonergic neurotransmission and involve AMPA receptors. |
Abstract
The emerging antidepressant effects of ketamine have inspired tremendous interest in its underlying neurobiological mechanisms, although the involvement of 5-HT in the antidepressant effects of ketamine remains unclear. The chronic restraint stress procedure was performed to induce depression-like behaviours in mice. OFT, FST, TST, and NSFT tests were used to evaluate the antidepressant-like effects of ketamine. Tph2 knockout or depletion of 5-HT by PCPA and 5,7-DHT were used to manipulate the brain 5-HT system. ELISA and fibre photometry recordings were used to measure extracellular 5-HT levels in the brain. 60 min after injection, ketamine (10 mg·kg-1, i.p.) produced rapid antidepressant-like effects and increased brain 5-HT levels. After 24 h, ketamine significantly reduced immobility time in TST and FST tests and increased brain 5-HT levels, as measured by ELISA and fibre photometry recordings. The sustained (24 h) but not rapid (60 min) antidepressant-like effects of ketamine were abrogated by PCPA and 5,7-DHT, or by Tph2 knockout. Importantly, NBQX (10 mg·kg-1, i.p.), an AMPA receptor antagonist, significantly inhibited the effect of ketamine on brain 5-HT levels and abolished the sustained antidepressant-like effects of ketamine in naïve or CRS-treated mice. This study confirms the requirement of serotonergic neurotransmission for the sustained antidepressant-like effects of ketamine, which appears to involve AMPA receptors, and provides avenues to search for antidepressant pharmacological targets.