Serotonergic transmission plays differentiated roles in the rapid and sustained antidepressant‐like effects of ketamine

Abstract Background and Purpose 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. Experimental approach 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. Key Results 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. Conclusion and Implications 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.