Enhancement of 5-HT2A receptor function and blockade of Kv1.5 by MK801 and ketamine: implications for PCP derivative-induced disease models

Lin, Haiyue; Kim, Jae Gon; Park, Sang Woong; Noh, Hyun Ju; Kim, Jeong‐Min; Yoon, Chang Yong; Woo, Nam-Sik; Cho, Sung-Il; Choi, Bok Hee; Sung, Dong Jun; Bae, Young Min

doi:10.1038/s12276-018-0073-6

Cited by 7 publications

(7 citation statements)

References 32 publications

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“…The Institutional Animal Care and Use Committee of Konkuk University approved this study. Mesenteric arterial rings and aortic rings were prepared as previously described 19,20 . The carotid arteries of male Sprague - Dawley rats (10 to 11 weeks old) were cut to exsanguinate the rats under deep ketamine-xylazine anesthesia or after exposure to 100% carbon dioxide.…”

Section: Methodsmentioning

confidence: 99%

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Estrogen modulates serotonin effects on vasoconstriction through Src inhibition

et al. 2018

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Estrogen has diverse effects on cardiovascular function, including regulation of the contractile response to vasoactive substances such as serotonin. The serotonin system recently emerged as an important player in the regulation of vascular tone in humans. However, hyperreactivity to serotonin appears to be a critical factor for the pathophysiology of hypertension. In this study, we examined the modulatory mechanisms of estrogen in serotonin-induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. 17β-Estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aortic strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes are not mediated by estrogen receptor. Patch-clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which was significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK293T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerts vasodilatory effects on serotonin-precontracted arteries via Src, implying a critical role for estrogen in the prevention of vascular hyperreactivity to serotonin.

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Section: Methodsmentioning

confidence: 99%

“…The isometric tension of arterial rings was measured as previously described 19,20 . The arterial rings were mounted vertically onto two L-shaped stainless steel wires in a 3-mL tissue chamber.…”

Section: Methodsmentioning

confidence: 99%

Estrogen modulates serotonin effects on vasoconstriction through Src inhibition

et al. 2018

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“…We have placed significant emphasis on the 5-HT2AR system throughout this paper, but it should be acknowledged that some prefer to extend the definition of psychedelics beyond action at this particular receptor. MDMA ( Siegel, 1986 ) and ketamine ( Bowdle et al, 1998 ) are two relevant examples in this regard ( Kuypers et al, 2018 ; Lin et al, 2018 ; Schmid et al., 2014 , Szlachta et al, 2017 ). Like the classic psychedelics, MDMA and ketamine have both been used as adjuncts to psychotherapy, with notable success ( McGirr et al, 2017 ; Sessa et al, 2019 ; Wilkinson et al, 2017 ).…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Pivotal mental states

2020

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This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.

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“…Previous reports demonstrated that the acute administration of ketamine, which shows rapid antidepressant effects, 47 , 48 enhances the 5-HT level in the prefrontal cortex 49–54 and the hippocampus. 55 Because ketamine is reported to suppress Kv channels, 56 , 57 we assumed that it enhances the spike firing of 5-HT neurons by blocking DTX-I-sensitive Kv1 channels. Bath-applied ketamine hydrochloride enhanced the spike firing in naïve rats ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Spike firing attenuation of serotonin neurons in learned helplessness rats is reversed by ketamine

Hashimoto

Yamawaki

Yamaoka

et al. 2021

Brain Communications

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Animals suffering from uncontrollable stress sometimes show low effort to escape stress [learned helplessness (LH)]. Changes in serotonin (5-HT) signaling are thought to underlie this behavior. Although the release of 5-HT is triggered by the action potential firing of dorsal raphe nuclei 5-HT neurons, the electrophysiological changes induced by uncontrollable stress are largely unclear. Herein, we examined electrophysiological differences among 5-HT neurons in naïve rats, LH rats and rats resistant to inescapable stress (non-LH). Five-week-old male Sprague–Dawley rats were exposed to inescapable foot shocks. After an avoidance test session, rats were classified as LH or non-LH. Activity-dependent 5-HT release induced by the administration of high potassium solution was slower in free-moving LH rats. Subthreshold electrophysiological properties of 5-HT neurons were identical among the three rat groups, but the depolarization-induced spike firing was significantly attenuated in LH rats. To clarify the underlying mechanisms, potassium (K+) channels regulating the spike firing were initially examined using naïve rats. K+ channels sensitive to 500 μM tetraethylammonium caused rapid repolarization of the action potential and the small conductance calcium-activated K+ channels (SK channels) produced afterhyperpolarization. Additionally, dendrotoxin-I (DTX-I), a blocker of Kv1.1 (encoded by Kcna1), Kv1.2 (encoded by Kcna2) and Kv1.6 (encoded by Kcna6) voltage-dependent K+ channels, weakly enhanced the spike firing frequency during depolarizing current injections without changes in individual spike waveforms in naïve rats. We found that DTX-I significantly enhanced the spike firing of 5-HT neurons in LH rats. Consequently, the difference in spike firing among the three rat groups was abolished in the presence of DTX-I. These results suggest that the upregulation of DTX-I-sensitive Kv1 channels underlies the firing attenuation of 5-HT neurons in LH rats. We also found that the antidepressant ketamine facilitated the spike firing of 5-HT neurons and abolished the firing difference between LH and non-LH by suppressing DTX-I-sensitive Kv1 channels. The DTX-I-sensitive Kv1 channel may be a potential target for developing drugs to control activity of 5-HT neurons.

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Enhancement of 5-HT2A receptor function and blockade of Kv1.5 by MK801 and ketamine: implications for PCP derivative-induced disease models

Cited by 7 publications

References 32 publications

Estrogen modulates serotonin effects on vasoconstriction through Src inhibition

Estrogen modulates serotonin effects on vasoconstriction through Src inhibition

Pivotal mental states

Spike firing attenuation of serotonin neurons in learned helplessness rats is reversed by ketamine

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