Intranasal (R, S)-ketamine delivery induces sustained antidepressant effects associated with changes in cortical balance of excitatory/inhibitory synaptic activity

微透析 氯胺酮 神经化学 NMDA受体 谷氨酸受体 药理学 抗抑郁药 抑制性突触后电位 兴奋性突触后电位 前额叶皮质 化学 敌手 鼻腔给药 麻醉剂 神经科学 海马体 麻醉 细胞外 医学 内分泌学 内科学 受体 心理学 生物化学 认知
作者
Thi Mai Loan Nguyen,Céline Defaix,Indira Mendez‐David,Laurent Tritschler,Isabelle Etting,Jean‐Claude Alvarez,Walid Choucha,Romain Colle,Emmanuelle Corruble,Denis J. David,Alain M. Gardier
出处
期刊:Neuropharmacology [Elsevier BV]
卷期号:225: 109357-109357 被引量:9
标识
DOI:10.1016/j.neuropharm.2022.109357
摘要

In 2019, an intranasal (IN) spray of esketamine SPRAVATO® was approved as a fast-acting antidepressant by drug Agencies US FDA and European EMA. At sub-anesthetic doses, (±)-ketamine, a non-competitive glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, increases the overall excitability of the medial prefrontal cortex (mPFC), an effect being essential for its rapid antidepressant activity. We wondered if this effect of ketamine could come from changes in the balance between neuronal excitation and inhibition (E/I balance) in the mPFC. Here, we performed a preclinical approach to study neurochemical and behavioral responses to a single IN ketamine dose in BALB/cJ mice, a strain more sensitive to stress. By using in vivo microdialysis, we measured cortical E/I balance as the ratio between glutamate to GABA extracellular levels 24 h post-ketamine. We found, for the first time, that E/I balance was shifted in favor of excitation rather than inhibition in the mPFC but more robustly with IN KET than with a single intraperitoneal (IP) dose. Increases in plasma and brain ketamine, norketamine and HNKs levels suggest different metabolic profiles of IP and IN ketamine 30 min post-dose. A significantly larger proportion of ketamine and HNKs in the brain are derived from the IN route 30 min post-dose. It may be linked to the greater magnitude in E/I ratio following IN delivery relative to IP at t24 h. This study suggests that both IP and IN are effective brain delivery methods inducing similar sustained antidepressant efficacy of KET, but the way they induced neurotransmitter changes is slightly different.
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