Action Of Ketamine Research Articles

Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit

Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive. We found that one day after the injection of a low dose of ketamine, long-term potentiation (LTP) in the nucleus accumbens (NAc) was impaired. Loss of LTP was maintained for 7 days and was not associated with an altered basal synaptic transmission mediated by AMPARs and N-methyl-D-aspartate receptors (NMDARs). Inhibition of mammalian target of rapamycin signaling with rapamycin did not prevent the ketamine-induced loss of LTP but inhibited LTP in saline-treated mice. However, ketamine blunted the increase in the phosphorylation of the GluA1 subunit of AMPARs at a calcium/calmodulin-dependent protein kinase II/protein kinase C site induced by an LTP induction protocol. Moreover, ketamine caused a persistent increased phosphorylation of GluA1 at a protein kinase A site. (2R,6R)-HNK also impaired LTP in the NAc. In dopaminergic neurons of the ventral tegmental area from ketamine- or (2R,6R)-HNK-treated mice, AMPAR-mediated responses were depressed, while those mediated by NMDARs were unaltered, which resulted in a reduced AMPA/NMDA ratio, a measure of long-term synaptic depression. These results demonstrate that a single injection of ketamine or (2R,6R)-HNK induces enduring alterations in the function of AMPARs and synaptic plasticity in brain regions involved in reward-related behaviors.

Behavioural and computational methods reveal differential effects for how delayed and rapid onset antidepressants effect decision making in rats

Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders. Until the recent discovery of the rapid onset antidepressant action of ketamine, pharmacological treatments for MDD were limited to conventional antidepressant drugs with delayed clinical efficacy. Using a judgement bias task, this study has investigated whether the temporal differences observed in patients would be reflected in affective biases and decision making behaviour in rodents. The diffusion model was also used to investigate the underlying decision making processes. Positive biases were induced in this task over timeframes that mirror the rapid versus delayed antidepressant efficacy of the drugs in clinical populations. Diffusion modelling revealed that the antidepressants tested also have different effects on decision making processes, suggesting they may act through different neurobiological substrates. This combination of behaviour and computational modelling may provide a useful approach to further investigate the mechanisms underlying rapid antidepressant effect and assess potential new treatments.

Differential Mechanisms Underlying Antidepressant Responses of Ketamine and Imipramine.

Ketamine, a noncompetitive NMDA receptor antagonist, exhibits rapid antidepressant actions, but the underlying mechanism remains obscure. AMPA receptor and cAMP response element-binding protein (CREB) are involved in the antidepressant actions of Ketamine and imipramine, a traditional tricyclic antidepressant. However, ketamine exerts its therapeutic actions much faster than imipramine. Understanding the discrepancy of antidepressant efficiency between ketamine and the traditional antidepressant is important for elucidating the mechanism underlying ketamine's fast-acting antidepressant responses as well as designing new rapid antidepressants. Here we show that the enhancement of the phosphorylation of CREB Ser133 and expression of CREB and glutamate receptor 1 (GluR1) are necessary for both ketamine's and imipramine's antidepressant actions, but the enhancements at early stage may account for the faster onset of ketamine's antidepressant action than imipramine. Notably, ketamine but not imipramine enhances CREBregulated transcription coactivator-1 (CRTC1) expression and induces potentiation of excitatory synaptic transmission at Schaffer collateral CA1 synapses, which indicates critical targets for unveiling ketamine's rapid antidepressant actions. Our study suggests that differential regulation of CRTC1 expression may contribute to the discrepancy of antidepressant efficacy between ketamine and imipramine, which may lead to a better understanding of ketamine's fast antidepressant responses.

A rapid and sensitive chiral LC–MS/MS method for the determination of ketamine and norketamine in mouse plasma, brain and cerebrospinal fluid applicable to the stereoselective pharmacokinetic study of ketamine

A novel method for the rapid and sensitive chiral determination of ketamine and norketamine in mouse plasma, brain and cerebrospinal fluid (CSF) was developed using liquid chromatography-tandem mass spectrometry (LC–MS/MS). This method reduces the required matrix volume, compared with a previously reported chiral assay method for ketamine and norketamine. The method involves the deproteinization of a small amount of biological matrix (corresponding to 5μL of plasma, 10mg of brain, or 2.5μL of CSF) using a water-miscible organic solvent containing 2H4-norketamine as an internal standard, the direct injection of the organic supernatant into an LC–MS/MS system, chiral separation on a CHIRALPAK AS-3R column (4.6mm i.d.×100mm, 3μm particles), and detection by electrospray ionization-selected reaction monitoring with an analytical run time of 5min. The lower limits of quantification for ketamine and norketamine enantiomers were 1ng/mL (plasma), 0.5ng/g (brain) and 2ng/mL (CSF). A good linearity of the calibration curves was obtained within a range of 1000-fold. The newly developed method was successfully used to determine the concentrations of ketamine and norketamine in mouse samples (plasma, brain and CSF) in a stereoselective manner. Therefore, this method is expected to contribute to the elucidation of the roles of ketamine and its metabolites in the antidepressant actions of ketamine.

Using Neuroimaging to Decipher the Mechanism of Action of Ketamine: A Pathway to Novel Therapeutics?

Using Neuroimaging to Decipher the Mechanism of Action of Ketamine: A Pathway to Novel Therapeutics?

Ketamine: Not Just for Pediatric Sedation?

Ketamine, an old drug with newly emerging clinical implications, offers an alternative agent for the management of acute pain in the pediatric emergency care setting. Subdissociative ketamine may be given by the intravenous route at doses of 0.3-0.8mg/kg or by the intranasal route at a dose of 1mg/kg. This review illustrates some of the gaps in our understanding between the mechanistic potential of ketamine and the actual evidence of clinical effects. The analgesic effects of ketamine result from a complex array of receptor interactions that modulate pain. The complex actions of ketamine make it a potentially superior agent to opioid medications, although data to support this are lacking. This article focuses on ketamine for acute pain and reviews the mechanism of action, dosing, routes of administration, adverse effects, and gaps in our current understanding of how the drug modulates pain.

Beyond Ketamine: New Approaches to the Development of Safer Antidepressants.

Background: Ketamine has been reported to exert rapid and sustained antidepressant effects in patients with depression, including patients with treatment-resistant depression. However, ketamine has several drawbacks such as psychotomimetic/dissociative symptoms, abuse potential and neurotoxicity, all of which prevent its routine use in daily clinical practice.Methods:Therefore, development of novel agents with fewer safety and usage concerns for the treatment of depression has been actively investigated. From this standpoint, searching for active substances (stereoisomers and metabolites) and agents acting on the N-methyl-D-aspartate (NMDA) receptor have recently gained much attention.Results: The first approach includes stereoisomers of ketamine, (R)-ketamine and (S)-ketamine. Although (S)-ketamine has been considered as the active stereoisomer of racemic ketamine, recently, (R)-ketamine has been demonstrated to exert even more prolonged antidepressant effects in animal models than (S)-ketamine. Moreover, ketamine is rapidly metabolized into several metabolites, and some metabolites are speculated as being active substances exerting antidepressant effects. Of such metabolites, one in particular, namely, (2R,6R)-hydroxynorketamine, has been reported to be responsible for the antidepressant effects of ketamine. The second approach includes agents acting on the NMDA receptor, such as glycine site modulators and GluN2B subunit-selective antagonists. These agents have been tested in patients with treatment-resistant depression, and have been found to exhibit rapid antidepressant effects like ketamine.Conclusion: The above approaches may be useful to overcome the drawbacks of ketamine. Elucidation of the mechanisms of action of ketamine may pave the way for the development of antidepressant that are safer, but as potent and rapidly acting as ketamine.

Isoflurane produces antidepressant effects and induces TrkB signaling in rodents

A brief burst-suppressing isoflurane anesthesia has been shown to rapidly alleviate symptoms of depression in a subset of patients, but the neurobiological basis of these observations remains obscure. We show that a single isoflurane anesthesia produces antidepressant-like behavioural effects in the learned helplessness paradigm and regulates molecular events implicated in the mechanism of action of rapid-acting antidepressant ketamine: activation of brain-derived neurotrophic factor (BDNF) receptor TrkB, facilitation of mammalian target of rapamycin (mTOR) signaling pathway and inhibition of glycogen synthase kinase 3β (GSK3β). Moreover, isoflurane affected neuronal plasticity by facilitating long-term potentiation in the hippocampus. We also found that isoflurane increased activity of the parvalbumin interneurons, and facilitated GABAergic transmission in wild type mice but not in transgenic mice with reduced TrkB expression in parvalbumin interneurons. Our findings strengthen the role of TrkB signaling in the antidepressant responses and encourage further evaluation of isoflurane as a rapid-acting antidepressant devoid of the psychotomimetic effects and abuse potential of ketamine.

Glutamate Deregulation in Ketamine-Induced Psychosis-A Potential Role of PSD95, NMDA Receptor and PMCA Interaction.

Ketamine causes psychotic episodes and is often used as pharmacological model of psychotic-like behavior in animals. There is increasing evidence that molecular mechanism of its action is more complicated than just N-methyl-D-aspartic acid (NMDA) receptor antagonism and involves interaction with the components of calcium homeostatic machinery, in particular plasma membrane calcium pump (PMCA). Therefore, in this study we aimed to characterize brain region-specific effects of ketamine on PMCA activity, interaction with NMDA receptor through postsynaptic density protein 95 (PSD95) scaffolding proteins and glutamate release from nerve endings. In our study, ketamine induced behavioral changes in healthy male rats consistent with psychotic effects. In the same animals, we were able to demonstrate significant inhibition of plasma membrane calcium ATPase (PMCA) activity in cerebellum, hippocampus and striatum. The expression level and isoform composition of PMCAs were also affected in some of these brain compartments, with possible compensatory effects of PMCA1 substituting for decreased expression of PMCA3. Expression of the PDZ domain-containing scaffold protein PSD95 was induced and its association with PMCA4 was higher in most brain compartments upon ketamine treatment. Moreover, increased PSD95/NMDA receptor direct interaction was also reported, strongly suggesting the formation of multiprotein complexes potentially mediating the effect of ketamine on calcium signaling. We further support this molecular mechanism by showing brain region-specific changes in PSD95/PMCA4 spatial colocalization. We also show that ketamine significantly increases synaptic glutamate release in cortex and striatum (without affecting total tissue glutamate content), inducing the expression of vesicular glutamate transporters and decreasing the expression of membrane glutamate reuptake pump excitatory amino acid transporters 2 (EAAT2). Thus, ketamine-mediated PMCA inhibition, by decreasing total Ca2+ clearing potency, may locally raise cytosolic Ca2+ promoting excessive glutamate release. Regional alterations in glutamate secretion can be further driven by PSD95-mediated spatial recruitment of signaling complexes including glutamate receptors and calcium pumps, representing a novel mechanism of psychogenic action of ketamine.

Antidepressant Actions of Ketamine Mediated by the Mechanistic Target of Rapamycin, Nitric Oxide, and Rheb.

The weeks/months it takes for traditional antidepressants to act pose an obstacle in the management of depression. Ketamine's prompt and sustained antidepressant effects constitute a major advance. Multiple studies implicate glutamatergic signaling to protein synthesis machinery and synapse formation in ketamine's antidepressant effects. Here we review evidence linking ketamine to glutamate receptor subtypes and protein homeostasis. We describe a signaling cascade wherein nitric oxide drives the formation of a ternary protein complex comprised of glyceraldehyde 3-phosphate dehydrogenase, seven in absentia homolog 1, and Ras homolog enriched in brain downstream of the glutamate N-methyl-D-aspartate receptor. Seven in absentia homolog 1 ubiquitylates and degrades Ras homolog enriched in brain leading to inhibition of mechanistic target of rapamycin. Ketamine inhibits this molecular cascade leading to activation of mechanistic target of rapamycin and, in turn, to antidepressant actions.

Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents

The glutamate N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of tests, focusing on antidepressant-like and dissociative-like effects in mice and rats. The minimum effective doses of KET and TIL were 10 mg/kg to reduce mouse forced swim test immobility and 15 mg/kg to reduce marble-burying behavior. However, at similar doses, both compounds diminished locomotor activity and disturbed learning processes in the mouse passive avoidance test and the rat novel object recognition test. KET and TIL also reduced social behavior and accompanying 50-kHz “happy” ultrasonic vocalizations (USVs) in rats. TIL (5–15 mg/kg) displayed additional anxiolytic-like effects in the four-plate test. Neither KET nor TIL affected pain response in the hot plate test. Examination of the “side effects” revealed that only at the highest doses investigated did both compounds produce motor deficits in the rotarod test in mice. While KET produced behavioral effects at doses comparable between species, in the rats, TIL was ~10 times more potent than in the mice. In summary, antidepressant-like properties of both KET and TIL are similar, as are their adverse effect liabilities. We suggest that TIL could be an alternative to KET as an antidepressant with an additional anxiolytic-like profile.

Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats

Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine.

80. Theories on the Mechanism of Action of Ketamine: From NMDA Receptor Inhibition to the (2R,6R)-HNK Metabolite

80. Theories on the Mechanism of Action of Ketamine: From NMDA Receptor Inhibition to the (2R,6R)-HNK Metabolite

Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials

BackgroundIdentifying clinical correlates associated with reduced suicidal ideation may highlight new avenues for the treatment of suicidal thoughts. Anhedonia occurs across psychiatric diagnoses and has been associated with specific neural circuits in response to rapid-acting treatments, such as ketamine. This analysis sought to evaluate whether reductions in suicidal ideation after ketamine administration were related to reduced levels of anhedonia, independent of depressive symptoms. MethodsThis post-hoc analysis included treatment-resistant patients with either major depressive disorder (MDD) or bipolar disorder (BD) from several clinical trials of ketamine. Anhedonia was assessed using a subscale of the Beck Depression Inventory (BDI) and the Snaith-Hamilton Pleasure Scale (SHAPS). The outcome of interest was suicidal ideation, as measured by a subscale of the Scale for Suicide Ideation (SSI5), one day post-ketamine administration. ResultsAnhedonia, as measured by the SHAPS, was associated with suicidal thoughts independent of depressive symptoms both before and after ketamine administration. One day post-ketamine administration, improvements on the SHAPS accounted for an additional 13% of the variance in suicidal thought reduction, beyond the influence of depressive symptoms. The BDI anhedonia subscale was not significantly associated with suicidal thoughts after adjusting for depressive symptoms. LimitationsData were limited to patients experiencing a major depressive episode and may not be generalizable to patients experiencing an active suicidal crisis. ConclusionsSuicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms. These results have implications for the potential mechanisms of action of ketamine on suicidal thoughts.

Ketamine, as adjuvant analgesics for patients with refractory cancer pain, does affect IL-2/IFN-γ expression of T cells in vitro?: A prospective, randomized, double-blind study.

Background:Ketamine has been used as an analgesic adjuvant with morphine in the treatment of refractory cancer pain recently. But both morphine and ketamine have been reported to produce a number of immunomodulatory effects. The current study was performed to assess whether the concentration of ketamine, as adjuvant analgesics for patient with refractory cancer pain, was related to its effect on T cells interleukin-2 (IL-2)/interferon-γ (IFN-γ) expression in vitro.Methods:Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood of patients with refractory cancer pain over a Ficoll-Hypaque density gradient. T cells were isolated from by positive selection using anti-CD3 beads. T cells were then treated with vehicle (C group), morphine (200 ng/mL, M group), morphine (200 ng/mL), and different dose of ketamine (100, 200, 1000 ng/mL; MK1, MK5, MK10 group) for 24 hours before stimulation with anti-CD3 and anti-CD28. Then supernatant IL-2 and IFN-γ protein analysis, quantitative reverse transcription polymerase chain reaction (RT-PCR) for IL-2 and IFN-γ were done.Results:There were no significant difference of supernatant IL-2 and IFN-γ among C group, M group, and MK1 group, but the mRNA of M group and MK1 group were decreased compared with C group (P < .05). Compared with C group, both of the supernatant protein and the mRNA of MK5 group and MK10 group were all significantly decreased (P < .01). Compared with M group, both of the supernatant protein and the mRNA of MK5 group and MK10 group were all decreased (P < .05), while supernatant IL-2 and the mRNA of MK10 group were significantly decreased (P < .01).Conclusion:In conclusion, we confirmed that just as morphine, ketamine dose-dependently suppressed IL-2 and IFN-γ of activated T lymphocyte of patients with refractory cancer pain in vitro, but the inhibitory action of low dose ketamine could be neglected.

Role of GPCRs and G‐αs in the antidepressant action of ketamine

Ketamine produces rapid and robust antidepressant effects in depressed patients within hours of administration, often when traditional antidepressant compounds have failed to alleviate symptoms even after 2 months of treatment. We hypothesized that ketamine would translocate Gas from lipid rafts to non‐raft microdomains, similarly to other antidepressants but with a distinct, abbreviated treatment duration. C6 glioma and C6 cells stably transfected with G‐αs‐GFP were treated with 10uM ketamine for 15 minutes, which translocated Gas from lipid raft domains to non‐raft domains. Other NMDA antagonist did not translocate Gas from lipid raft to non‐raft domains. The ketamine induced Gas plasma membrane redistribution allows increased functional coupling of Gas and adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Furthermore, increased intracellular cAMP increased phosphorylation of cAMP response element‐binding protein (CREB), which, in turn, increased BDNF expression. These results reveal a novel antidepressant mechanism mediated by acute ketamine treatment in glial cells that may contribute to ketamine's powerful antidepressant effect.

Rapid antidepressant effect of ketamine correlates with astroglial plasticity in the hippocampus.

Astroglia contribute to the pathophysiology of major depression and antidepressant drugs act by modulating synaptic plasticity; therefore, the present study investigated whether the fast antidepressant action of ketamine is reflected in a rapid alteration of the astrocytes' morphology in a genetic animal model of depression. S-Ketamine (15mg·kg-1 ) or saline was administered as a single injection to Flinders Line (FSL/ FRL) rats. Twenty-four hours after the treatment, perfusion fixation was carried out and the morphology of glial fibrillary acid protein (GFAP)-positive astrocytes in the CA1 stratum radiatum (CA1.SR) and the molecular layer of the dentate gyrus (GCL) of the hippocampus was investigated by applying stereological techniques and analysis with Imaris software. The depressive-like behaviour of animals was also evaluated using forced swim test. FSL rats treated with ketamine exhibited a significant reduction in immobility time in comparison with the FSL-vehicle group. The volumes of the hippocampal CA1.SR and GCL regions were significantly increased 1day after ketamine treatment in the FSL rats. The size of astrocytes in the ketamine-treated FSL rats was larger than those in the FSL-vehicle group. Additionally, the number and length of the astrocytic processes in the CA1.SR region were significantly increased 1day following ketamine treatment. Our results support the hypothesis that astroglial atrophy contributes to the pathophysiology of depression and a morphological modification of astrocytes could be one mechanism by which ketamine rapidly improves depressive behaviour.

Ketamine Promotes Neurite Growth and Recovers Dexamethasone-Induced Mobility Decrease in Cultured Hippocampal Cells

The “plasticity hypothesis” proposes that major depression is caused by morphological and biochemical modifications in neurons and astrocytes and that the illness is at least partially associated with modifications of cellular communications between these cells. In this study we examined effects of Ketamine, an NMDA antagonist that was conventionally used as an anesthetic, on dexamethasone-treated neurons. Several clinical trials have shown that this drug has very potent anti-depressive properties, becoming effective within a few hours. Ketamine has also been shown to have fast effect on the neuronal plasticity, including synaptogenesis and dendrite formation. In this project, we studied its morphodynamic effects in hippocampal neuronal cultures by motion-, neurite growth analysis and cluster formation. Time-lapse images taken over 48 hours and the resulting videos were analyzed by several newly developed complex algorithms for morphometry and cell mobility. Dexamethasone, a synthetic corticosteroid, was used to induce depression-associated changes in cultured hippocampal neurons. Results show that ketamine significantly neutralized dexamethasone-induced reduction of cell mobility and cell cluster formation. Neither dexamethasone nor ketamine had strong effects on the density and growth of neurites. In summary, given the complex actions of ketamine on morphodynamic parameters in cultured neurons, its mechanism as an anti-depressant cannot be explained with its NMDA-antagonistic properties alone but implies additional impact on the formation of communication networks and morphology related pathways.

Ketamine Inhibition of Pentameric Ligand-Gated Ion Channels - Insights from Molecular Dynamics Simulations

The anesthetic ketamine is well known as a non-competitive antagonist of N-methyl-D-aspartate receptors (NMDARs). However, not all the clinical effects of ketamine can be fully explained by its inhibition of NMDARs. An alternative mode of ketamine action is through inhibition of pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine receptors. Ketamine inhibits the bacterial pLGIC from Gloeobacter violaceus (GLIC) and the ketamine-GLIC co-crystallized structure was determined previously.

The Inhibitory Effects of Ketamine on Human Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Action Potential in Rabbit Sinoatrial Node

Aims: To investigate the effects of ketamine on human hyperpolarization-activated cyclic nucleotide-gated (hHCN) 1, 2, 4 channel currents expressed in Xenopus oocytes and spontaneous action potentials (APs) of rabbit sinoatrial node (SAN). Methods: The 2-electrode voltage clamp and standard microelectrode techniques were respectively applied to record hHCN channels currents expressed in Xenopus oocytes and APs of SAN separated from rabbit heart. Results: Ketamine (1-625 µmol/L) blocked hHCN1, 2, and 4 currents with IC₅₀ of 67.0, 89.1, and 84.0 µmol/L, respectively, in a concentration-dependent manner. The currents were rapidly blocked by ketamine and partially recovered after washout. The steady-state activation curves of hHCN1, 2, and 4 currents demonstrated a concentration-dependent shift to the left and the rates of activation were significantly decelerated. But ketamine blocked hHCN channels in a voltage-independence and non-use-dependent manner, and did not modify the voltage dependence of activation and reversal potentials. Furthermore, ketamine suppressed phase-4 spontaneous depolarization rate in isolated rabbit SAN and decreased the beat rates in a concentration-dependent manner. Conclusion: Ketamine could inhibit hHCN channels expressed in Xenopus oocytes in a concentration-dependent manner as a close-state blocker and decrease beat rates of isolated rabbit SAN. This study may provide novel insights into other unexplained actions of ketamine.