Malikowska-Racia Natalia, Golebiowska Joanna, Nikiforuk Agnieszka, Khoo Shaun Yon-Seng, Popik Piotr
Behavioral Neuroscience and Drug Development, Maj Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, 31-343 Kraków, Poland.
Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Canada.
Eur Neuropsychopharmacol. 2023 Feb;67:37-52. doi: 10.1016/j.euroneuro.2022.11.007. Epub 2022 Dec 5.
(S)-ketamine-induced rapid-acting antidepressant effects have revolutionized the pharmacotherapy of major depression; however, this medication also produces psychotomimetic effects such as timing distortion. While (R)-ketamine produces fewer dissociative effects, its antidepressant actions are less studied. Depression is associated with time overestimation (i.e., subjectively, time passes slowly). Our recent report suggests that while (S)-ketamine induces an opposite effect, i.e., time underestimation, the (R)-isomer does not affect timing. It has been suggested that opioid receptors are involved in the antidepressant effect of ketamine. In the present study we tested (R)- and (S)-ketamine, and fluoxetine as a positive control in the differential-reinforcement-of-low-rate (DRL) 72-s schedule of reinforcement in male rats following naloxone pretreatment. DRL classic metrics as well as peak deviation analyses served to determine antidepressant-like actions and those associated with timing. We report antidepressant-like effects of (S)-ketamine (30-60 mg/kg) that resemble fluoxetine's (2.5-10 mg/kg), as both compounds increased reinforcement rate and peak location (suggesting increased performance), reduced premature responses (suggesting time underestimation) and decreased Weber's fraction (suggesting increased timing precision). (R)-ketamine (30, but not 60 mg/kg) increased only the reinforcement rate and peak location but did not affect timing. Only fluoxetine decreased burst responses, suggesting decreased impulsivity. Naloxone pretreatment did not block ketamine enantiomers' actions, but unexpectedly, increased fluoxetine' performance. Thus, while all three medications produced antidepressant-like effects in DRL 72-s, fluoxetine- and (S)- but not (R)- ketamine-induced time underestimation (the subject experiences the time as passing quickly). The potentiation of DRL performance of fluoxetine by naloxone was unexpected and warrants clinical studies.
(S)-氯胺酮诱导的快速起效抗抑郁作用彻底改变了重度抑郁症的药物治疗；然而，这种药物也会产生拟精神病效应，如时间扭曲。虽然(R)-氯胺酮产生的解离效应较少，但其抗抑郁作用的研究较少。抑郁症与时间高估有关（即主观上时间过得很慢）。我们最近的报告表明，虽然(S)-氯胺酮会诱导相反的效应，即时间低估，但(R)-异构体不会影响时间感知。有人认为阿片受体参与了氯胺酮的抗抑郁作用。在本研究中，我们在纳洛酮预处理后的雄性大鼠的低强化率（DRL）72秒强化程序中测试了(R)-和(S)-氯胺酮，以及作为阳性对照的氟西汀。DRL经典指标以及峰值偏差分析用于确定抗抑郁样作用和与时间感知相关的作用。我们报告了(S)-氯胺酮（30-60毫克/千克）的抗抑郁样效应与氟西汀（2.5-10毫克/千克）相似，因为这两种化合物都提高了强化率和峰值位置（表明表现增强），减少了过早反应（表明时间低估）并降低了韦伯分数（表明时间精度提高）。(R)-氯胺酮（30毫克/千克，但60毫克/千克时无此效应）仅提高了强化率和峰值位置，但不影响时间感知。只有氟西汀减少了爆发反应，表明冲动性降低。纳洛酮预处理并未阻断氯胺酮对映体的作用，但出乎意料的是，增强了氟西汀的表现。因此，虽然所有三种药物在DRL 72秒程序中都产生了抗抑郁样效应，但氟西汀和(S)-氯胺酮而非(R)-氯胺酮诱导了时间低估（受试者感觉时间过得很快）。纳洛酮对氟西汀DRL表现的增强作用出乎意料，值得进行临床研究。
