Repeated ketamine anesthesia during neurodevelopment upregulates hippocampal activity and enhances drug reward in male mice

Cui, Jianchen; Ju, Xianshu; Lee, Yulim; Hong, Boohwi; Kang, Hyojin; Han, Kihoon; Shin, Won-Ho; Park, Ji-Ho; Lee, Min Joung; Kim, Yoon Hee; Ko, Youngkwon; Heo, Jun Young; Chung, Woosuk

doi:10.1038/s42003-022-03667-4

Cited by 5 publications

(3 citation statements)

References 65 publications

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“…Similarly to our study, tolerance to repeated treatment with ketamine was found regarding its anesthetic efficacy [40][41][42][43] and psychotomimetic effects [44]. The tolerance reported in our study may indicate that repeated treatment of patients suffering from depression with ketamine or ketamine enantiomers would progressively result in fewer side effects.…”

Section: Plos Onesupporting

confidence: 87%

Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats

Elersič,

Banjac,

Živin

et al. 2024

PLoS ONE

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Ketamine has gained significant attention as a fast-acting antidepressant. However, ketamine is also associated with undesirable side effects. In our preclinical study, we explored the behavioral effects of ketamine enantiomers at subanesthetic doses. During repeated intermittent treatment, we examined locomotor stimulation and sensitization, ataxia, and expression of natural behaviors (grooming and rearing). Male Wistar rats were subcutaneously treated repeatedly with either 5 mg/kg of R-ketamine or S-ketamine, 15 mg/kg of R-ketamine, S-ketamine or racemic ketamine, 30 mg/kg of racemic ketamine or saline every third day for three weeks (seven treatments overall). After the first treatment, only 15 mg/kg of S-ketamine induced locomotor stimulation, and both 15 mg/kg of S-ketamine and 30 mg/kg of racemic ketamine induced ataxia. Upon repeated administration, doses of 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine, as well as 30 mg/kg of racemic ketamine, stimulated locomotion. 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine additionally resulted in locomotor sensitization. The last administration of 15 mg/kg of S-ketamine, 15 mg/kg of racemic ketamine, and 30 mg/kg of racemic ketamine resulted in ataxia. In the case of 15 mg/kg of S-ketamine, ataxic effects were significantly weaker in comparison to the effects from the first administration, indicating tolerance. Natural behaviors were attenuated after 5 and 15 mg/kg of S-ketamine and 15 and 30 mg/kg of racemic ketamine. Neither of the R-ketamine doses produced such an effect. We conclude that S-ketamine has a stronger behavioral effect than R-ketamine.

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Section: Plos Onesupporting

confidence: 87%

Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats

Elersič,

Banjac,

Živin

et al. 2024

PLoS ONE

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“…The thickness of dendrites influences the transmission of postsynaptic potentials by affecting electrical resistance, with thicker dendrites propagating signals more quickly than thin dendrites (Loopuijt et al , 2007;Li et al , 2019). It is reported that increased dendritic diameter in COX-2 knockin mice may result in excitatory signaling imbalances in the cerebellum (Leeet al , 2017;Sohal & Rubenstein, 2019;Cui et al , 2022). In our study, we demonstrate a significant decrease in dendritic spine density in COX-2KO mice compared to WT ones, suggesting the critical role of COX-2 on synaptic plasticity in the hippocampus CA1.…”

Section: Discussionmentioning

confidence: 99%

The Crucial Role of Hippocampus Cyclooxygenase-2 Plays in Synaptic Plasticity and Memory

Guo

et al. 2022

Preprint

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It is generally accepted that Cyclooxygenase-2 (COX-2) is activated to cause inflammation. However, COX-2 is also constitutively expressed at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Although some evidence suggests that COX-2 release during neuronal signaling may be pivotal for regulating the function of memory, the significance of constitutively expressed COX-2 in neuron is still unclear. This research aims to discover the role of COX-2 in memory beyond neuroinflammation and to determine whether the inhibition of COX-2 can cause cognitive dysfunction by influencing dendritic plasticity and its underlying mechanism. The cognitive ability was assessed by novel object recognition task (NORT) and Morris water maze (MWM) test. Immunofluorescence, Golgi-cox staining were used to observe dendritic synaptic. Gamma oscillation in hippocampus CA1 was performed by Tetrode in-vivo recording. Prostaglandins were measured by HPLC/mass spectrometry. We observed the expressions of cAMP/ BDNF pathway proteins in hippocampus and N2a cells by Elisa and western blot. We found COX-2 gene knockout could significantly impact the learning and memory ability; reduce the expression of PSD95 in the neuron; cause synaptic disorder; influence gamma oscillation and reduce the expression PGE2, cAMP, p-PKA, p-CREB and BDNF in the hippocampus. It suggests COX-2 may play a critical role in learning and memory ability in modulating postsynaptic membrane PSD95, regulating synaptic plasticity and gamma oscillation in the hippocampus CA1 by regulating COX-2/BDNF signaling pathway.

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“…Ketamine has a strong addiction potential via inducing SA and CPP [ 85 , 86 , 87 ]. However, there is no systematic review of the specific mechanisms of ketamine addiction.…”

Section: Molecular Mechanism Of Non-opioid Anesthetic Drug Addictionmentioning

confidence: 99%

Non-Opioid Anesthetics Addiction: A Review of Current Situation and Mechanism

Deng,

Wu,

Gao

et al. 2023

Brain Sciences

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Drug addiction is one of the major worldwide health problems, which will have serious adverse consequences on human health and significantly burden the social economy and public health. Drug abuse is more common in anesthesiologists than in the general population because of their easier access to controlled substances. Although opioids have been generally considered the most commonly abused drugs among anesthesiologists and nurse anesthetists, the abuse of non-opioid anesthetics has been increasingly severe in recent years. The purpose of this review is to provide an overview of the clinical situation and potential molecular mechanisms of non-opioid anesthetics addiction. This review incorporates the clinical and biomolecular evidence supporting the abuse potential of non-opioid anesthetics and the foreseeable mechanism causing the non-opioid anesthetics addiction phenotypes, promoting a better understanding of its pathogenesis and helping to find effective preventive and curative strategies.

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Repeated ketamine anesthesia during neurodevelopment upregulates hippocampal activity and enhances drug reward in male mice

Cited by 5 publications

References 65 publications

Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats

Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats

The Crucial Role of Hippocampus Cyclooxygenase-2 Plays in Synaptic Plasticity and Memory

Non-Opioid Anesthetics Addiction: A Review of Current Situation and Mechanism

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