Ketamine-Induced Prefrontal Serotonin Release Is Mediated by Cholinergic Neurons in the Pedunculopontine Tegmental Nucleus

Kinoshita, Hidenori; Nishitani, Naoya; Nagai, Yuma; Andoh, Chihiro; Asaoka, Nozomi; Kawai, Hiroyuki; Shibui, Norihiro; Nagayasu, Kazuki; Shirakawa, Hisashi; Nakagawa, Takayuki; Kaneko, Shuji

doi:10.1093/ijnp/pyy007

Cited by 28 publications

(25 citation statements)

References 26 publications

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“…The mechanism underlying the antidepressant-like effect of ketamine may involve increased activity in the descending mPFC-DRN glutamatergic connections which physiologically activate DRN 5-HT projection cells [15]. Interestingly, it has been shown that activation of 5-HT DRN projection cells by ketamine is mediated by the cholinergic projection from the pedunculopontine tegmental nucleus [45]. However, these studies were performed using naïve animals, not subjected to stress or corticosterone administration.…”

Section: Discussionmentioning

confidence: 99%

Ketamine Administration Reverses Corticosterone-Induced Alterations in Excitatory and Inhibitory Transmission in the Rat Dorsal Raphe Nucleus

et al. 2019

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Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, exerts rapid antidepressant effects in human patients and ameliorates depressive-like behavioral effects of chronic stress in animal models. Chronic stress and elevated corticosterone levels have been shown to modify serotonin (5-HT) neurotransmission, and ketamine’s antidepressant-like activity involves a 5-HT-dependent mechanism. However, it is not known if and how ketamine affects the electrophysiological characteristics of neurons and synaptic transmission within the dorsal raphe nucleus (DRN), the main source of 5-HT forebrain projections. Our study was aimed at investigating the effects of a single ketamine administration on excitatory and inhibitory transmission in the DRN of rats which had previously been administered corticosterone twice daily for 7 days. Spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) were then recorded from DRN projection cells in ex vivo slice preparations obtained 24 h after ketamine injection. Repeated corticosterone administration increased sEPSC frequency and decreased sIPSC frequency in DRN projection cells. There were no changes either in the amplitude of postsynaptic currents or in the excitability of these cells. In slices prepared from rats with ketamine administered after the end of corticosterone treatment, the frequencies of sEPSCs and sIPSCs were similar to those in control preparations. These data indicate that a single administration of ketamine reversed the effects of corticosterone on excitatory and inhibitory transmission in the DRN.

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Section: Discussionmentioning

confidence: 99%

Ketamine Administration Reverses Corticosterone-Induced Alterations in Excitatory and Inhibitory Transmission in the Rat Dorsal Raphe Nucleus

et al. 2019

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“…At “therapeutically” relevant concentrations in mice, ketamine inhibited serotonin clearance and produced antidepressant-like effects in wild-type mice, but not in SERT−/− and PMAT−/− mice. Taken together with existing literature [ 15 , 16 , 17 , 18 , 19 , 45 , 47 , 48 , 49 , 50 ], a critical role for serotonin and its inhibition of uptake via SERT and PMAT cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. These findings pave the way for future experiments to interrogate the role, and mechanism of action, of SERT and PMAT in the antidepressant actions of ketamine, which will add to literature suggesting that concurrent blockade of SERT and “uptake-2” transporters, such as PMAT, has greater antidepressant efficacy than SSRIs alone [ 21 , 23 , 24 ].…”

Section: Discussionmentioning

confidence: 96%

“…The importance of serotonin is perhaps best exemplified by reports from several groups who found that the antidepressant-like effect of ketamine is lost when serotonin is depleted via PCPA treatment [ 16 , 17 , 18 ]. Consistent with an important role for serotonin in the antidepressant effects of ketamine, multiple studies have shown that ketamine increases extracellular serotonin, yet the mechanism(s) by which this occurs remains unclear [ 15 , 18 , 46 , 47 , 48 , 49 , 50 ]. Our studies point to ketamine-induced inhibition of serotonin clearance via SERT and PMAT as potential mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice

Bowman

Vitela

Clarke

et al. 2020

IJMS

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Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine’s ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. Combined with what is already known about ketamine’s action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine’s abuse potential but have superior efficacy in treating depression.

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“…Dental cement and a small metal peg were used to secure the guide cannula on the skull, then the duct cover were putted and tightened. After 3-4 d recovery period, microdialysis experiments were performed as previously described 38…”

Section: Microdialysismentioning

confidence: 99%

Electro-acupuncture Alleviates METH Withdrawal-induced Spatial Memory Deficits by Restoring Astrocyte-drived Glutamate Uptake in dCA1

Shi

et al. 2020

Preprint

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24Methamphetamine (METH) is frequently abused drug and produces cognitive deficits. METH could 25 induce hyper-glutamatergic state in the brain, which could partially explain METH-related cognitive 26 deficits, but the synaptic etiology remains unclear. Here, we investigated the role of dCA1 tripartite 27 synapses and the potential therapeutic effects of electro-acupuncture (EA) in the METH withdrawal-28 induced spatial memory deficits. METH withdrawal weakened astrocytic capacity of Glu uptake, but 29 failed to change Glu release from dCA3, resulting in hyper-glutamatergic excitotoxicity at dCA1 30 tripartite synapses. By restoring the astrocytic capacity of Glu uptake, EA treatments suppressed the 31 hyper-glutamatergic state and normalized the excitability of postsynaptic neuron in dCA1, finally 32 alleviated spatial memory deficits in METH withdrawal mice. These findings indicate that astrocyte 33 at tripartite synapses might be a novel target for developing therapeutic interventions against METH-34 associated cognitive disorders, and EA represent a promising non-invasive therapeutic strategy for 35 the management of drugs-caused neurotoxicity.36 3

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Ketamine-Induced Prefrontal Serotonin Release Is Mediated by Cholinergic Neurons in the Pedunculopontine Tegmental Nucleus

Cited by 28 publications

References 26 publications

Ketamine Administration Reverses Corticosterone-Induced Alterations in Excitatory and Inhibitory Transmission in the Rat Dorsal Raphe Nucleus

Ketamine Administration Reverses Corticosterone-Induced Alterations in Excitatory and Inhibitory Transmission in the Rat Dorsal Raphe Nucleus

Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice

Electro-acupuncture Alleviates METH Withdrawal-induced Spatial Memory Deficits by Restoring Astrocyte-drived Glutamate Uptake in dCA1

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