Ketamine Isomers Research Articles

Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers

Ketamine and its (S)-enantiomer show distinct psychological effects that are investigated in psychiatric research. Its antidepressant activity may depend on the extent and quality of these psychological effects which may greatly differ between the enantiomers.Previous data indicate that the (S)-ketamine isomer is a more potent anesthetic than (R)-ketamine. In contrast, in subanesthetic doses (R)-ketamine seems to elicit fewer dissociative and psychotomimetic effects compared to (S)-ketamine.In this randomized double-blind placebo-controlled trial the effects of (R/S)-ketamine and (S)-ketamine on standardized neuropsychological and psychopathological measures were compared. After an initial bolus equipotent subanesthetic doses of (R/S)- and (S)-ketamine or placebo were given by continuous intravenous infusion to three groups of 10 healthy male volunteers each (n = 30).(R/S)-Ketamine and (S)-ketamine produced significant psychopathology and neurocognitive impairment compared to placebo. No significant differences were found between (R/S)-ketamine and (S)-ketamine. (S)-Ketamine administration did not result in reduced psychopathological symptomatology compared to (R/S)-ketamine as suggested by previous studies. However, this study revealed a somewhat more “negatively experienced” psychopathology with (S)-ketamine, which opens questions about potential “protective effects” associated with the (R)-enantiomer against some psychotomimetic effects induced by the (S)-enantiomer.As the antidepressant effect of ketamine might depend on a pleasant experience of altered consciousness and perceptions and avoidance of anxiety, the ideal ketamine composition to treat depression should include (R)-ketamine. Moreover, since preclinical data indicate that (R)-ketamine is a more potent and longer acting antidepressant compared to (S)-ketamine and (R/S)-ketamine, randomized controlled trials on (R)-ketamine and comparative studies with (S)-ketamine and (R/S)-ketamine are eagerly awaited.

Anesthesia of Agoutis (Dasyprocta prymnolopha) with Dextroketamine and Midazolam

Background: Research has increasingly focused on wild animals, and this requires the use of chemical restraints that are safe for both the species and the team involved. Dextroketamine is the levorotatory ketamine isomer that has been used on domestic species as an alternative that is more potent and safer than the racemic form. Midazolam is a benzodiazepine that induces muscle relaxation and minimal cardiorespiratory changes. The purpose of this study was to determine whether a combination of dextroketamine and midazolam can be safely used for the chemical restraint of agoutis (Dasyprocta prymnolopha), and the effects of this protocol on physiological and anesthetic parameters. Materials, Methods & Results: This study was carried out under conditions similar to those found for wild animals in captivity or in zoos. A pre-evaluation was also made to compare the baseline values of this study with those of other studies on the same species. Nine healthy adult agoutis were used, weighing between 1.5 kg and 2 kg. All the parameters were evaluated and recorded before the drugs were applied, and this was considered the baseline moment (M0). The dextroketamine and midazolam combination was then administered intramuscularly, in the same syringe, in dosages of 15 mg/kg and 0.5 mg/kg, respectively. Successive evaluations were made every 10 min over a period of 40 min (M10, M20, M30 and M40). The latency stage of anesthesia, effective stage and recovery stage were observed. Heart rate (HR) and breathing frequency (f), body temperature (BT), systolic blood pressure (SBP), peripheral oxygen saturation (SpO2) and electrocardiogram were recorded. HR and SBP showed no significant difference between moments. Breathing frequency (f) showed a significant decline at M10 and M20 when compared to baseline values (P < 0.05). BT decreased from the moment the drugs were administered until the end of the experimental period, with a significant difference between M0 and M40, and M10 and M40 (P < 0.05). SpO2 decreased significantly at M10 and M20 when compared to baseline values (P < 0.01). There was no significant difference in the duration and amplitude of the P wave or in the duration of the QRS complex, QT interval and amplitude of the R wave. Regarding the PR interval, there was a significant difference only at M40 when compared to baseline values (P < 0.05). No arrhythmia was observed. An evaluation of the effects of anesthesia indicated that the animals had an average latency stage of 2 min, an effective stage of 87 min, and an average recovery stage of 111 min. Adverse effects observed during the anesthetic recovery period consisted of tearing, salivation, tongue protrusion, vocalization and chewing reflex. Discussion: The results indicated that the association of anesthetic drugs under study caused minimal changes in the animals’ physiological parameters, except for the breathing frequency (f), which declined considerably, resulting in a reduction in SpO2, which was compensated during the study. In addition, there was a rapid onset of restraint and a satisfactory duration. Thus, from the cardiorespiratory standpoint, the combination of dextroketamine and midazolam in the doses used provides a safe anesthetic protocol for agoutis (Dasyprocta prymnolopha) and can be used for the chemical restraint of these animals for the performance of non-invasive and short-term procedures.

P.458 Acute antidepressant effects of different ketamine isomers in rats submitted to maternal separation animal model: A pilot study

P.458 Acute antidepressant effects of different ketamine isomers in rats submitted to maternal separation animal model: A pilot study

Preclinical Assessment of the Abuse Potential of the Isomers of Ketamine

BackgroundRacemic (R,S)‐ketamine produces a rapid and long‐lasting antidepressant response in treatment resistant patients with major depressive disorder (MDD). However, the production of psychotomimetic effects and a propensity for abuse have limited its therapeutic use. The individual isomers of ketamine are being investigated for treatment of MDD with proponents stating each isomer has an improved side‐effect profile relative to the racemate. The goal of this project was to evaluate the abuse‐related behavioral side effects of (S)‐ and (R)‐ketamine by determining their reinforcing effects in a self‐administration procedure and (R,S)‐ketamine‐like subjective effects in a drug discrimination procedure.MethodsFor the drug discrimination study, subjects were male Sprague‐Dawley rats trained to discriminate 5.6 mg/kg ketamine from saline in standard two‐lever operant chambers during daily 15‐min sessions. Correct responding was reinforced with food pellet delivery under a fixed ratio (FR) 10 schedule. Generalization tests with saline or different doses of (S)‐ketamine (0.3 – 10 mg/kg), (R)‐ketamine (3 mg/kg – 30 mg/kg) and (R,S)‐ketamine (0.3 – 5.6 mg/kg) were conducted twice weekly with training sessions intervening. For the self‐administration study, subjects were four male Rhesus monkeys (Macaca mulatta) surgically implanted with a chronic catheter in a major vein. Monkeys were trained to respond for intravenous infusions of 56 μg/kg/inf (R,S)‐ketamine solution under a FR 30 schedule. Solutions of saline or different doses of (R,S)‐ketamine (10 to 170 μg/kg/inf ) and (S)‐ketamine (10 to 100 μg/kg/inf ) were substituted for the training solution for four consecutive sessions. Any dose which maintained responding above saline levels was also tested under a progressive ratio schedule across sessions.ResultsIn the discrimination procedure, the racemate and both isomers dose‐dependently generalized from the training dose with one or more doses producing full substitution. Comparing ED50 values, (S)‐ketamine was approximately 1.9‐fold more potent than (R,S)‐ketamine and 4‐fold more potent than (R)‐ketamine for substitution and rate suppression. In the self‐administration study, one or more doses of the racemate and both isomers maintained levels of responding significantly above saline levels. When the work requirement was increased, both isomers maintained self‐administration behavior across a number of sessions with break points, the highest ratio maintaining responding above mean saline levels, reaching up to 200 responses/infusion.ConclusionsThe data show that both (R)‐ and (S)‐ketamine share discriminative stimulus effects with (R,S)‐ketamine and therefore would be predicted to produce racemic ketamine‐like subjective effects in humans. In the self‐administration procedure, both (R)‐ and (S)‐ketamine serves as positive reinforcers of behavior under FR conditions with peak intake levels and break points comparable to the racemic form. Overall, based on these outcomes we would predict that both of the ketamine isomers would produce use‐limiting side effects similar to (S,R)‐ketamine, including psychotomimetic effects and abuse liability, in humans.Support or Funding InformationNIDA grant R01 DA037287This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Differential role of nitric oxide in the psychedelic symptoms induced by racemic ketamine and esketamine in human volunteers

BackgroundAnimal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(–)-ketamine isomers, or esketamine, containing just the S(+)-isomer. MethodsIn this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 μg kg−1 min−1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point. ResultsSodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion. ConclusionsThese data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(–)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms. Clinical trial registrationNTR 5359.

Ketamine enantiomers in the rapid and sustained antidepressant effects.

Recent evidence has suggested that the N-methyl-D-aspartate receptor antagonist ketamine shows significant therapeutic effects in major depression and bipolar disorder. This effect is especially important in treatment-resistant depression and depression with suicidal ideation. In this review we explain the mechanism of action, drug efficacy, and the side effects of ketamine; the antidepressive effects of ketamine; the individual effects of ketamine isomers, R(-) ketamine and S(+) ketamine; the effects of the combination of ketamine with electroconvulsive therapy; and the possible use of ketamine in treating depression.

The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents.

Methoxetamine (MXE) is a ketamine analog sold online that has been subject to widespread abuse for its dissociative and hallucinogenic effects. Previous studies have shown that MXE has high affinity for the phencyclidine (PCP) binding site located within the channel pore of the NMDA receptor (NMDAR), but little is known about its behavioral effects. Dissociative anesthetics such as ketamine and PCP produce a characteristic behavioral profile in rats that includes locomotor hyperactivity and disruption of prepulse inhibition (PPI) of acoustic startle. The goal of the present investigation was to determine whether MXE produces PCP-like effects in Sprague-Dawley rats using the PPI paradigm and the behavioral pattern monitor (BPM), which enables analyses of patterns of locomotor activity and investigatory behavior. PPI studies were conducted with several other uncompetitive NMDAR antagonists that produce dissociative effects in humans, including PCP, the S-(+) and R-(-) isomers of ketamine, and N-allylnormetazocine (NANM; SKF-10,047). MXE disrupted PPI when administered at 3 and 10mg/kg SC. The rank order of potency of MXE and the other test compounds in the PPI paradigm (PCP > MXE > S-(+)-ketamine > NANM > R-(-)-ketamine) parallels their affinities for the PCP binding site reported in the literature. When tested in the BPM, 10mg/kg MXE induced locomotor hyperactivity, reduced the number of rearings, increased the roughness of locomotor paths, and produced perseverative patterns of locomotion. Administration of PCP (2.25 and 6.75mg/kg, SC) produced a similar profile of effects in the BPM. These results indicate that MXE produces a behavioral profile similar to that of other psychotomimetic uncompetitive NMDAR antagonists. Our findings support the classification of MXE as a dissociative drug and suggest that it likely has effects and abuse potential similar to that of PCP and ketamine.

R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine

The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is one of the most attractive antidepressants for treatment-resistant major depressive disorder (MDD). Ketamine (or RS (±)-ketamine) is a racemic mixture containing equal parts of R (−)-ketamine and S (+)-ketamine. In this study, we examined the effects of R- and S-ketamine on depression-like behavior in juvenile mice after neonatal dexamethasone (DEX) exposure. In the tail suspension test (TST) and forced swimming test (FST), both isomers of ketamine significantly attenuated the increase in immobility time, seen in DEX-treated juvenile mice at 27 and 29h respectively, after ketamine injections. In the 1% sucrose preference test (SPT), both isomers significantly attenuated the reduced preference for 1% sucrose consumption in DEX-treated juvenile mice, 48h after a ketamine injection. Interestingly, when immobility times were tested by the TST and FST at day 7, R-ketamine, but not S-ketamine, significantly lowered the increases in immobility seen in DEX-treated juvenile mice. This study shows that a single dose of R-ketamine produced rapid and long-lasting antidepressant effects in juvenile mice exposed neonatally to DEX. Therefore, R-ketamine appears to be a potent and safe antidepressant relative to S-ketamine, since R-ketamine may be free of psychotomimetic side effects.

Ketamine*

Ketamine*

Protective effects of S(+) ketamine and atropine against lethality and brain damage during soman-induced status epilepticus in guinea-pigs

Soman poisoning is known to induce full-blown tonic–clonic seizures, status epilepticus (SE), seizure-related brain damage (SRBD) and lethality. Previous studies in guinea-pigs have shown that racemic ketamine (KET), with atropine sulfate (AS), is very effective in preventing death, stopping seizures and protecting sensitive brain areas when given up to 1 h after a supra-lethal challenge of soman. The active ketamine isomer, S(+) ketamine (S-KET), is more potent than the racemic mixture and it also induces less side-effects. To confirm the efficacy of KET and to evaluate the potential of S-KET for delayed medical treatment of soman-induced SE, we studied different S-KET dose regimens using the same paradigm used with KET. Guinea-pigs received pyridostigmine (26 μg/kg, IM) 30 min before soman (62 μg/kg, 2 LD 50, IM), followed by therapy consisting of atropine methyl nitrate (AMN) (4 mg/kg, IM) 1 min following soman exposure. S-KET, with AS (10 mg/kg), was then administered IM at different times after the onset of seizures, starting at 1 h post-soman exposure. The protective efficacy of S-KET proved to be comparable to KET against lethality and SRBD, but at doses two to three times lower. As with KET, delaying treatment by 2 h post-poisoning greatly reduced efficacy. Conditions that may have led to an increased S-KET brain concentration (increased doses or number of injections, adjunct treatment with the oxime HI-6) did not prove to be beneficial. In summary, these observations confirm that ketamine, either racemic or S-KET, in association with AS and possibly other drugs, could be highly effective in the delayed treatment of severe soman intoxication.

Using the BOLD MR signal to differentiate the stereoisomers of ketamine in the rat

Rationale: Ketamine is a chiral molecule that is reported to model aspects of schizophrenia. Objectives: To investigate the stereospecificity of the isomers of ketamine using pharmacological magnetic resonance imaging (phMRI) in order to further understand ketamine's pharmacodynamic actions. Method: Responses to 25 mg kg −1 S(+) isomer, R(−) isomer and racemic ketamine in independent groups of Sprague–Dawley rats were investigated using a prepulse inhibition paradigm, locomotor observations, MRI and 2-deoxyglucose techniques. Results: Racemic ketamine and the S(+) isomer were both capable of disrupting sensorimotor gating as measured using prepulse inhibition and produced a longer period of hyperlocomotion comparative to the R(−) isomer. In contrast, large alterations in the BOLD MR signal were observed with R(−) isomer, whereas S(+) isomer and racemate precipitated more localized BOLD signal changes predominantly in cortical, hippocampal and hindbrain regions. Glucose utilization rates in conscious animals are in agreement with previously published data and verify the BOLD responses in the racemic group. However, no significant changes in glucose utilization were observed in the anesthetized cohort. Conclusions: Ketamine and its isomers have stereospecific effects on sensorimotor gating and locomotion that correlate with the enantiomer's affinity for the NMDA receptor. It would appear that anesthesia, as required for preclinical MRI procedures, may interact with and potentially attenuate the drug's response. Although analysis of the main effect of isomers in comparison to each other or the racemate offers an alternative analysis method that should be less susceptible to anesthetic interactions, only the R(−) isomer comparative to the racemate offers significant differences of interest.

Stereoselective effects of ketamine on dopamine, serotonin and noradrenaline release and uptake in rat brain slices

Ketamine (2-(2-chlorophenyl)-(1-methylamino)-cyclohexanone) is a rapid-acting dissociative general anaesthetic whose hallucinogenic properties have made it a popular drug of abuse. Ketamine comprises two optical isomers, with differing pharmacology. In the present study, the effects of (+)- and (−)-ketamine on stimulated efflux and reuptake of dopamine (DA), noradrenaline (NA) and serotonin (5-HT) were compared in isolated superfused slices of the rat caudatoputamen (CPu), ventral bed nucleus of the stria terminalis (BSTV) or dorsal raphe nucleus (DRN), respectively. Monoamine efflux was elicited by local electrical stimulation (20 pulses, 100 Hz trains) at tungsten microelectrodes and measured at adjacent carbon fibre microelectrodes using fast cyclic voltammetry (FCV). In CPu (+)-ketamine increased stimulated DA efflux and slowed DA reuptake in a concentration-dependent manner (25–200 μM). At 100 μM (+)-ketamine increased DA efflux by 109±20% (mean±S.E.M., n=13) of control values after 30 min ( P<0.001 versus control) and prolonged uptake half-time ( t 1/2) by 76±38% ( n=9, P<0.001) of control. In contrast (−)-ketamine (100 μM) had no effect on DA efflux or uptake. In DRN, both isomers (100 μM) increased stimulated 5-HT efflux. (−)-Ketamine had a larger effect ( P<0.001), an 88±15% increase in 5-HT efflux ( n=9) versus 46±10% ( n=8) for the (+)-isomer. The isomers had similar effects on 5-HT uptake, increasing t 1/2 by approximately 200%. No evidence of stereospecificity was seen in BSTV: both isomers had small effects (+)- and (−)-ketamine (100 μM) increasing NA efflux by 43±10% ( n=7, P<0.001) and 29±8% ( n=7, P<0.001), respectively. The isomers also had identical effects on NA uptake, each increasing uptake t 1/2 by approximately 100%. In summary, our data show that the optical isomers of ketamine have strikingly different stereospecificity for the monoamine systems and one might predict, therefore, a different psychotomimetic potential.

Ketamine: the past 30 years and its future

There are two isomers of ketamine: S(+) ketamine and R(-) ketamine. Effects of this drug are mediated by N-methyl-D-aspartate (NMDA), opioid and muscarinic receptors. Due to its high lipid solubility and low protein binding, ketamine is extensively distributed in the body. Ketamine metabolism is mediated by hepatic microsomal enzymes. Ketamine causes increased intracranial pressure, bronchodilation and stimulation of cardiovascular system. It is used for premedication, sedation, induction and maintenance of general anesthesia. Ketamine is an ideal anesthetic agent for trauma victims, patients with hypovolemic and septic shock, patients with pulmonary diseases. Even subanesthetic doses of ketamine have analgesic effects, so ketamine is also recommended for postoperative analgesia. Recent results show that ketamine is not always effective as an analgesic in treatment of chronic pain and that some side effects limit its use in patients with chronic pain. Combination of ketamine and midazolam can be very useful and safe for sedation and pain relief in intensive care patients, especially during ventilator management. Ketamine may be the anesthetic of choice for painful procedures in intensive care units.

Ketamine and MK-801 Decrease Acetylcholine Release in the Pontine Reticular Formation, Slow Breathing, and Disrupt Sleep

Ketamine induces a dissociated state of consciousness by binding to the phencyclidine binding site within the ion channel gated by the N-methyl-D-aspartate (NMDA) receptor. The brain regions and neurotransmitter systems mediating ketamine-induced alterations in arousal remain incompletely understood. This study used in vivo microdialysis to test the hypothesis that ketamine alters acetylcholine (ACh) release in the medial pontine reticular formation (mPRF). Acetylcholine (ACh) release, sleep, and breathing were quantified following systemic ketamine administration. Microdialysis was used to deliver the NMDA-channel blocker dizocilpine maleate (MK-801) and the R(-)-isomer of ketamine into the mPRF while measuring ACh release. N/A. N/A. N/A. Systemically administered ketamine disrupted normal sleep-cycle organization, reduced mPRF ACh release, and significantly slowed rate of breathing. Dialysis delivery of MK-801 to the mPRF significantly decreased respiratory rate and mPRF ACh release. Dialysis delivery to the mPRF of the R(-)-ketamine isomer significantly decreased mPRF ACh release. Decreased mPRF ACh release caused by systemically administered ketamine was mimicked by mPRF dialysis delivery of MK-801 and the R(-)-ketamine isomer. These data are consistent with the conclusion that systemically administered ketamine may alter arousal and breathing, in part, by altering cholinergic neurotransmission in the mPRF.

Cardiovascular Effects of Ketamine Isomers in Rabbit Isolated Heart Model

Cardiovascular Effects of Ketamine Isomers in Rabbit Isolated Heart Model

Ketamine isomers suppress superantigen-induced proinflammatory cytokine production in human whole blood.

To investigate the efficacy of S(+)-ketamine and R(-)-ketamine on staphylococcal enterotoxin B (SEB)-induced tumour necrosis factor (TNF)-, interleukin (IL)-6, and IL-8 production in human whole blood in vitro. After Ethics Committee approval and informed consent, blood samples were obtained from ten healthy volunteers and diluted with five volumes of RPMI 1640. After adding different doses of ketamine isomers (0-1000 microM), the blood was stimulated with SEB (10 ng x mL(-1)). After a six-hour incubation period, the plasma TNF- activity was determined by the L929 cell cytotoxic assay and IL-6 and IL-8 concentrations were measured using an enzyme-linked immunoassay. Ketamine isomers significantly suppressed SEB-induced TNF- production at concentrations exceeding 50 microM. Ketamine isomers at concentrations exceeding 100 microM also significantly suppressed SEB-induced IL-6 production. Furthermore, ketamine isomers at concentrations exceeding 500 microM significantly suppressed SEB-induced IL-8 production. There were no significant differences between the suppressive effects of S(+)-ketamine and R(-)-ketamine on SEB-induced proinflammatory cytokine production. This study demonstrated that ketamine isomers suppressed SEB-induced TNF-, IL-6, and IL-8 production in human whole blood.

Nonstereoselective inhibition of neuronal nicotinic acetylcholine receptors by ketamine isomers.

We have found that racemic ketamine strongly inhibits the current mediated through neuronal nicotinic acetylcholine receptors (nAchRs) in PC12 cells, a rat pheochromocytoma cell line. Ketamine stereoisomers have different potencies for the anesthetic action, with the S-enantiomer being about 3 times as potent as the R-enantiomer. The purpose of this study was to clarify if the inhibitory effects of ketamine on neuronal nAchRs contribute to their anesthetic effect. We compared potencies of ketamine enantiomers for neuronal nAchR inhibition with those for the anesthetic action. S(+) and R(-) ketamine inhibited the nicotine-induced whole-cell current in a dose-dependent manner at the membrane potential of -60 mV. They accelerated the current decay, resulting in the larger effects on the nondesensitized current than on the peak current. There was no significant difference in the concentrations for 50% inhibition between the stereoisomers. The ketamine isomers exerted the same effects on single-channel properties estimated from analysis of the nicotine-induced current noise. These results indicate that the inhibitory action of ketamine isomers on neuronal nAchRs is not stereoselective. Although our findings do not deny possible involvement of these receptors in ketamine anesthesia, they suggest that inhibition of neuronal nAchRs is not primarily responsible for the anesthetic action of this anesthetic. We found that inhibition of neuronal nicotinic acetylcholine receptors by ketamine is not stereoselective in PC12 cells. The result suggests that this effect does not directly correlate with the anesthetic action of ketamine.

Nonstereoselective Inhibition of Neuronal Nicotinic Acetylcholine Receptors by Ketamine Isomers

We have found that racemic ketamine strongly inhibits the current mediated through neuronal nicotinic acetylcholine receptors (nAchRs) in PC12 cells, a rat pheochromocytoma cell line. Ketamine stereoisomers have different potencies for the anesthetic action, with the S-enantiomer being about 3 times as potent as the R-enantiomer. The purpose of this study was to clarify if the inhibitory effects of ketamine on neuronal nAchRs contribute to their anesthetic effect. We compared potencies of ketamine enantiomers for neuronal nAchR inhibition with those for the anesthetic action. S(+) and R(−) ketamine inhibited the nicotine-induced whole-cell current in a dose-dependent manner at the membrane potential of −60 mV. They accelerated the current decay, resulting in the larger effects on the nondesensitized current than on the peak current. There was no significant difference in the concentrations for 50% inhibition between the stereoisomers. The ketamine isomers exerted the same effects on single-channel properties estimated from analysis of the nicotine-induced current noise. These results indicate that the inhibitory action of ketamine isomers on neuronal nAchRs is not stereoselective. Although our findings do not deny possible involvement of these receptors in ketamine anesthesia, they suggest that inhibition of neuronal nAchRs is not primarily responsible for the anesthetic action of this anesthetic. Implications We found that inhibition of neuronal nicotinic acetylcholine receptors by ketamine is not stereoselective in PC12 cells. The result suggests that this effect does not directly correlate with the anesthetic action of ketamine.

The stereoselective effects of ketamine isomers on heteromeric N-methyl-D-aspartate receptor channels.

The effects of S(+)- and R(-)-ketamine on heteromeric N-methyl-D-aspartate receptor channels were investigated on the epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1, and epsilon4/zeta1 channels expressed in Xenopus oocytes. S(+)-ketamine inhibited all four epsilon/zeta channels more effectively than R(-)-ketamine. The inhibitor concentrations for half-control response for S(+)-ketamine were quite similar among the four channels with 0.44-0.56 microM. However, the inhibitor concentrations for half-control response for R(-)-ketamine varied slightly among the four channels with 1.0 microM for epsilon2/zeta1 and epsilon3/zeta1 channels and 1.9-2.0 microM for epsilon1/zeta1 and epsilon4/zeta1 channels. Thus, the potency ratio of S(+)- and R(-)-ketamine for heteromeric channels was only slightly different among the epsilon/zeta channels. The potency order and ratio of ketamine isomers for inhibition of N-methyl-D-aspartate receptor channels may not be so different between the brain region and the developmental stage.

The Stereoselective Effects of Ketamine Isomers on Heteromeric N-Methyl-d-Aspartate Receptor Channels

The effects of S(+)- and R(–)-ketamine on heteromeric N-methyl-d-aspartate receptor channels were investigated on the ε1/ζ1, ε2/ζ1, ε3/ζ1, and ε4/ζ1 channels expressed in Xenopus oocytes. S(+)-ketamine inhibited all four ε/ζ channels more effectively than R(–)-ketamine. The inhibitor concentrations for half-control response for S(+)-ketamine were quite similar among the four channels with 0.44–0.56 μM. However, the inhibitor concentrations for half-control response for R(–)-ketamine varied slightly among the four channels with 1.0 μM for ε2/ζ1 and ε3/ζ1 channels and 1.9–2.0 μM for ε1/ζ1 and ε4/ζ1 channels. Thus, the potency ratio of S(+)- and R(–)-ketamine for heteromeric channels was only slightly different among the ε/ζ channels. Implications The potency order and ratio of ketamine isomers for inhibition of N-methyl-d-aspartate receptor channels may not be so different between the brain region and the developmental stage.