As a phencyclidine (PCP) analog, ketamine can generate rapid-onset and substantial anesthetic effects. Contrary to traditional anesthetics, ketamine is a dissociative anesthetic and can induce loss of consciousness in patients. Recently, the subanaesthetic dose of ketamine was found to produce rapid-onset and lasting antidepressant effects.

Aim

However, how different concentrations of ketamine can induce diverse actions remains unclear. Furthermore, the molecular mechanisms underlying the NMDAR-mediated anesthetic and antidepressant effects of ketamine are not fully understood.

Method

In this review, we have introduced ketamine and its metabolism, summarized recent advances in the molecular mechanisms underlying NMDAR inhibition in the anesthetic and antidepressant effects of ketamine, explored the possible functions of NMDAR subunits in the effects of ketamine, and discussed the future directions of ketamine-based anesthetic and antidepressant drugs.

Result

Both the anesthetic and antidepressant effects of ketamine were thought to be mediated by N-methyl-D-aspartate receptor (NMDAR) inhibition.

Conclusion

The roles of NMDARs have been extensively studied in the anaesthetic effects of ketamine. However, the roles of NMDARs in antidepressant effects of ketamine are complicated and controversial.

1 INTRODUCTION

Over 300 million surgeries are performed annually,^{1, 2} and anesthesia is used worldwide to deal with these painful surgeries.² The use of general anesthesia is characterized by amnesia, analgesia, unconsciousness, and immobility.³ As a dissociative anesthetic, ketamine produces rapid-onset effects while retaining consciousness.⁴ However, the psychological side effects of ketamine during the recovery period and the high potential of abuse prevent its clinical application.^{5, 6} Recently, a subanaesthetic dose of ketamine was found to generate rapid-onset and long-lasting antidepressant effects.^{7, 8} Low concentrations of ketamine can induce rapid antidepressant effects within 1 h of a single infusion that last for over 1 week, which has been used for treatment-resistant depression (TRD).^{9, 10} Nonetheless, ketamine has the potential for abuse and psychological side effects, restricting its clinical use for treating depression. Therefore, investigating the molecular mechanisms underlying the anesthetic and antidepressant effects of ketamine would benefit ketamine-based drug discovery as well as decrease the abuse potential and side effects of ketamine.

Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist, and NMDAR inhibition is assumed to mediate the anesthetic and antidepressant effects of ketamine.^11-13 Accordingly, several NMDAR antagonists, such as nitrous oxide (N₂O, laughing gas) and MK-801, can produce effects similar to those of ketamine.^{11, 14} Although the antidepressant effects of ketamine are sustained for weeks,^{15, 16} the half-life of ketamine is 2–4 h, and it metabolizes rapidly and extensively to norketamine (NK), hydroxynorketamine (HNK), and dehydronorketamine (DHNK).^{17, 18} Therefore, the metabolites of ketamine are assumed to mediate its long-term effects. Moreover, NK can induce anesthetic effects, and HNK can produce antidepressant effects, indicating that the metabolism of ketamine affects its pharmacology. However, in a later study, HNK was found to be inessential for the antidepressant effects of (R)-ketamine,¹⁹ suggesting that the molecular mechanisms underlying the ketamine-induced anesthetic and antidepressant effects need further investigation.

NMDAR inhibition is the primary presumptive molecular mechanism underlying the effects of ketamine.^{13, 20} Both ketamine and its metabolite NK bind NMDARs and produce anesthetic effects.²¹ However, the local anesthetic effects of ketamine may also be mediated by voltage-gated sodium channels.^{22, 23} HNK can enhance the activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and mediate the antidepressant effects of ketamine in an NMDAR-independent manner.^24-26 By contrast, although HNK can bind NMDARs,²⁷ it does not produce antidepressant effects.^{19, 28} The presumptive mechanisms underlying NMDAR inhibition in the effects of ketamine are controversial and much more complicated. In this review, we have focused on the NMDAR-induced anesthetic and antidepressant effects of ketamine. First, we have introduced ketamine and its metabolites. Then, we have summarized the recent advances in the NMDAR-mediated anesthetic and antidepressant effects of ketamine and have surveyed the possible roles of different NMDAR subunits in the effects of ketamine. Finally, we have discussed the future perspectives on the clinical application of ketamine.

2 KETAMINE

Phencyclidine (PCP) was designed and synthesized for use as a dissociative anesthetic in 1958.²⁹ However, due to its strong psychomotor, rewarding, and reinforcing properties, PCP and its analogs were abused worldwide as psychoactive substances, although their psychopharmacological properties have not yet been fully uncovered.³⁰

Psychomimetic adverse effects were found to have limited the clinical usefulness of PCP. Since then, more PCP analogs have been designed to reduce these psychotomimetic and cognitive adverse effects.³¹ Ketamine (Ci581) (2-(O-chlorophenyl)-2-methylamino cyclohexanone) is one of over 200 analogs of PCP and exhibits promising anesthetic and antidepressant effects.³² Ketamine has two optical isomers (enantiomers): S-(+)-ketamine and R-(−)-ketamine.³³ In this review, ketamine has been referred to as a racemic mixture. Ketamine, or “Special K” causes a dissociative state of relaxed well-being and hallucinogenic effects at subanaesthetic doses.³⁴ Moreover, the well-known adverse psychological effects of ketamine would impair cognition and memory, which have not yet been solved.³⁵ As a rapid-acting drug, the half-life of ketamine is 2–4 h. Ketamine is catalyzed through N-demethylation by cytochrome P450 enzymes and can generate the initial metabolite (R, S)-(NK) (80%) in human plasma.¹² NK is metabolized into DHNK through dehydrogenation, and ketamine can also be rapidly metabolized into HK and 6-HNK through hydroxylation and N-demethylation.^36-38 To further understand the metabolism and pharmacokinetics of ketamine, please see the relevant review.¹⁷

3 THE ANESTHETIC EFFECTS OF KETAMINE

The general anesthetic effects of ketamine include amnesia, analgesia, unconsciousness, and immobility.³ As a dissociative anesthetic, ketamine causes loss of orthostatic reflexes but not consciousness, indicating that the patients remain awake with their eyes open.^{39, 40} As a PCP analog, ketamine exerts anesthetic effects in a dose-dependent manner by acting on the central nervous system. In 1965, Edward Domino used ketamine as an anesthetic in humans, and the results showed that ketamine was short-acting with psychotropic effects.⁴¹ Traditionally, ketamine is administered in a dose of 1–4.5 mg/kg intravenously or 6.5–13 mg/kg intramuscularly to induce anesthetic effects in humans, depending on the patient's age and the desired clinical effects.^{34, 42} Ketamine can disrupt frontal–parietal communication and induce anesthetic effects.^43-46 Ketamine also affects the cardiovascular system by acting on the sympathetic nervous system. The anesthetic effects of ketamine are dose-dependent. However, repeated administration can result in ketamine resistance.⁴⁷ S-(+)-ketamine is more effective and long-lasting than a racemic mixture of S- and R-enantiomers. Both (R, S)-ketamine and its initial metabolite (R, S)-NK penetrate the blood–brain barrier, thereby producing anesthetic effects. However, the other metabolite (2R, 6R; 2S, 6S)-HNK can also penetrate the blood–brain barrier but does not induce any anesthetic effects.⁴⁸

Although ketamine can block voltage-gated sodium channels and induce local anesthetic effects,^{22, 23} the general anesthetic effects of ketamine are supposedly mediated by NMDAR inhibition. Accordingly, HNK without any anesthetic effects showed a lower binding affinity for NMDARs compared with ketamine and NK.^{26, 49} The anesthetic dose of ketamine caused neuronal apoptosis and cognitive deficits in rodents and rhesus monkeys,^50-53 suggesting that the use of ketamine as a dissociative anesthetic should be strictly scrutinized.

4 ANTIDEPRESSANT EFFECTS OF KETAMINE

Similar to PCP, the subanaesthetic doses of ketamine produce antidepressant effects. Seven patients with major depression were intravenously administered 0.5 mg/kg ketamine at Yale University in 2000,⁷ the results showed that the depressive symptoms were significantly improved within the next 2 test days. This was the first clinical trial of ketamine for major depression.^{7, 34} Some studies also indicated that ketamine could improve bipolar depression and TRD.^{54, 55} Patients with TRD do not respond to the currently available antidepressant pharmacological therapies, and this might result in a high risk of suicidal behaviors.⁵⁶ Thus, novel rapid-response antidepressant drugs are needed for these patients. The previous pilot studies indicated that R-(−)-ketamine produces rapid and significant effects in the treatment of TRD and bipolar depression.^{57, 58} The response rates of patients with bipolar depression and TRD to ketamine at 4 h were >50%.^{59, 60} Ketamine can affect the functional connectivity between the cortex and striatum in depressed individuals and thereby produce antidepressant effects,⁶¹ although some contradictory results have been reported.⁶² Interestingly, patients with depression with dissociative effects were found to have experienced greater improvements in their depressive symptoms upon ketamine treatment,^{63, 64} indicating that the dissociative side effects could help predict the antidepressant efficacy of ketamine in these patients. However, subsequent analysis and studies suggested no relationship between the dissociative side effects and the antidepressant effects of ketamine.^{10, 65} Furthermore, the dissociative side effects of ketamine are acute and dissipate in 80 min, and the antidepressant effects occur within 110 min and last for 1 week,^{66, 67} suggesting that the ketamine-mediated dissociative side effects and antidepressant effects depend on diverse signaling pathways. The elimination half-life of ketamine is 2–4 h,^{12, 68, 69} and the antidepressant effects of ketamine can last for up to 1 week. Therefore, the molecular mechanisms underlying the long-lasting antidepressant effects of ketamine need further exploration.

Besides, the antidepressant effects of ketamine are dose-dependent. There is clear evidence of the efficacy of 0.5 and 1.0 mg/kg intravenously administered subanaesthetic doses of ketamine in TRD, whereas 0.1 mg/kg intravenously administered doses of ketamine cannot significantly improve the health of patients with TRD.^{70, 71} The molecular mechanisms underlying the dose-dependent antidepressant effects of ketamine remain elusive.

5 THE BLOCKAGE EFFECTS OF KETAMINE ON NMDARs

As a non-competitive NMDAR antagonist, ketamine can bind the PCP-binding region of NMDARs in the Ca²⁺ channel pore, resulting in the deactivation of eukaryotic elongation factor 2 (eEF2) kinase (CaMK III), thereby inducing protein synthesis through mTORC1 and executing antidepressant effects (Figure 1).⁷² In line with this, some non-ketamine NMDAR antagonists such as MK-801 (dizocilpine), N₂O (laughing gas) and CPP (3-(2-carboxypiperazin-4-yl) propyl-1-phosponic acid) can also produce fast-acting antidepressant effects.^{11, 72-74} However, some non-ketamine NMDAR antagonists such as memantine, lanicemine (AZD6765), and MK-0657 (CERC-301) do not produce robust antidepressant effects.^{75, 76} Furthermore, the antidepressant effects of NMDAR antagonists are species- and dose-dependent.^75-77 Taken together, these findings suggested that the roles of NMDARs in ketamine-mediated antidepressant effects are complicated. Interestingly, the anesthetic doses of ketamine do not induce antidepressant effects, of which the NMDARs are fully blocked by the high concentrations of ketamine.⁷⁸ The subanaesthetic doses of ketamine can partially block the NMDARs, and over 50% of NMDARs are unblocked,^{79, 80} which may contribute to the psychiatric side effects of ketamine.

Details are in the caption following the image — **FIGURE 1**
Open in figure viewer PowerPoint

Ketamine and its metabolites inhibit NMDARs. The inhibition of NMDARs by ketamine and its metabolites affects protein synthesis through the actions of BDNF, mTORC1, and ERK.

The binding affinity of S-(+)-ketamine to NMDARs is fourfold greater than that of the other enantiomer R-(−)-ketamine, indicating that S-(+)-ketamine has greater potency in anesthetic effects,⁸¹ although it is more expensive than racemic ketamine.³² The psychomimetic side effects of R-(−)-ketamine were mild as compared with those of S-(+)-ketamine in depressed mice.⁸² However, the psychomimetic side effects of S-(+)-ketamine were mostly mild compared with the racemic mixture ketamine in the patients with major TRD.⁸³ These inconsistent data from mouse and small-scale human clinical trials suggest that the psychopharmacological properties of ketamine may be different in different species. Thus, the molecular mechanisms underlying the anesthetic and antidepressant effects of ketamine are complex and need further investigation.

5.1 N-methyl-D-aspartate receptor

Typically, NMDARs are composed of two GluN1 and two identical GluN2 (2A-D)/GluN3 (A-B) subunits and assemble as di-heteromeric complexes.^{84, 85} However, NMDARs can also consist of two GluN1 and two different GluN2/GluN3 subunits, which are tri-heteromeric complexes.^{85, 86} The developmental switch from GluN2B- to GluN2A-containing NMDARs at the hippocampal synapses suggests that NMDAR subunits change during development.^{87, 88} All the NMDAR subunits consist of four domains: the NTD (N-terminal domain) is a clamshell-like structure, and the ABD (agonist D-serine/glycine and glutamate-binding domain) can bind D-serine/glycine (GluN1 and GluN3) and glutamate (GluN2), the TMD (transmembrane domain) can form the ion channel, and the CTD (C-Terminal Domain) mediates the synaptic localization of NMDARs and the downstream Ca²⁺ signaling transduction.^{89, 90} These agonists are required but are not efficient in the activation of NMDARs because of Mg²⁺ blockage in the NMDARs at rest membrane potential.⁹¹ Once the postsynaptic membranes are depolarised, Mg²⁺ is released, leading to the opening and activation of NMDARs required for learning and memory.^92-95 Ketamine can bind the PCP site in the pore of NMDARs, which is partially overlapped with the Mg²⁺-binding site.¹² Therefore, ketamine only blocks the Mg²⁺-released open NMDARs but not the closed NMDARs with Mg²⁺ blockage.⁹⁶

5.2 NMDARs mediated the anesthetic effects of ketamine

Ketamine and its principal metabolite NK are active agents, whereas the other metabolites are inactive compounds.^{21, 97} However, the anesthetic effects of NK were significantly decreased as compared with those of ketamine, which indicated that the metabolism of ketamine to NK attenuated the anesthetic effects.²¹ Nevertheless, NK has a lower potential for abuse and side effects than ketamine, especially the S(+) enantiomer.⁹⁸ Interestingly, ketamine's other principal metabolite HNK did not generate any anesthetic effects.²¹ Given that NMDAR inhibition is the major mechanism underlying the anesthetic effects of ketamine, the binding affinity of NMDARs to ketamine (Ki = 530 nM) should be greater than that to NK and HNK. Furthermore, S-ketamine and its metabolite S-NK contain five times and eight times higher affinity for NMDARs than the R-enantiomers, respectively.⁹⁹ Therefore, these S-enantiomers have more potency in their anesthetic effects compared with the R-enantiomers. Mechanistically, ketamine binds the PCP site in the NMDAR channel and then inhibits the activation of NMDARs, which is assumed to be the molecular mechanisms through which ketamine induces the anesthetic effects. In line with this, the anesthetic gases xenon and isoflurane can bind the glycine site of NMDARs and inhibit the activation of NMDARs,^100-102 indicating that NMDAR inhibition produces anesthetic effects. In terms of the NMDAR subunits, GluN1 is an obligatory subunit, and is expressed ubiquitously throughout the brain.⁸⁵ The GluN2A and GluN2B subunits are abundant in the central nervous system. However, the GluN2C and GluN2D subunits are restrictedly expressed in the cerebellum.⁸⁵ GluN3 subunits are not required for anesthetic activity.¹⁰³ Therefore, the NMDAR subunits GluN1 and GluN2A-2B may meet the three criteria of targets relevant to anesthetic action.¹⁰⁴ Both GluN1 and GluN2B knockout mice die shortly during the postnatal period, so the GluN2A knockout mice are the only global knockout mice to prove the essential role of NMDARs in the anesthetic effect of ketamine.¹⁰⁵ Given that the GluN1, GluN2A, and GluN2B subunits were found to be lost in anti-NMDA encephalitis,^106-108 such patients should be avoided when using ketamine to induce general anesthesia in the future.¹⁰⁹

5.3 NMDARs were involved in the antidepressant effects of ketamine

The expression of the GluN2A and GluN2B subunits was reduced in the major depression,¹¹⁰ the regulation of ellagic acid on the expression of the GluN2A and GluN2B subunits might have affected antidepressant-like effects.¹¹¹ Taken together, these studies suggested the possible regulation of NMDARs on major depression. The prevailing hypothesis of the antidepressant effects of ketamine was the NMDAR inhibition-mediated activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors).¹¹² Therefore, metabolites with high affinity to NMDARs should have high-antidepressant potency. However, the antidepressant effects of (R-)-ketamine were greater than those of (S-)-ketamine,⁸² although the affinity of (R-)-ketamine (Ki =1340 nM) to NMDARs was less than that of (S-)-ketamine (Ki = 465 nM).^{113, 114} In line with this, 50 μM ketamine metabolite (2R, 6R)-HNK produced more rapid-acting and reliable antidepressant effects than its enantiomer (2S, 6S)-HNK.²⁴ Furthermore, the NMDAR antagonist MK-801 (Ki = 3.49 nM) exhibited a higher affinity for NMDARs compared with ketamine (Ki = 530 nM), and MK-801 did not exhibit more rapid antidepressant effects than ketamine. Taken together, these data suggest that the antidepressant effects of ketamine might be NMDARs-independent. Furthermore, the ketamine metabolite (2R, 6R; 2S, 6S)-HNK (Ki > 10,000 nM for NMDARs) could rapidly cross the blood–brain barrier. Given that (2R, 6R; 2S, 6S)-HNK could generate antidepressant effects, but not anesthetic effects, NMDARs might mainly contribute to the anesthetic effects than to the antidepressant effects of ketamine. Although previous studies have indicated that NMDAR inhibition does not mediate the rapid and sustained antidepressant actions of ketamine,^{24, 25} NMDAR inhibition was found to control hyperlocomotion.²⁴ Given the confounding factor of hyperlocomotion in the depression mice models,¹¹⁵ NMDARs might play a role in the antidepressant effects of ketamine. In line with this, the following study indicated that the 50 μM ketamine metabolite (2R, 6R)-HNK could inhibit NMDARs, thereby mediating the antidepressant effects of ketamine.²⁷ These two inconsistent studies used different concentrations of (2R, 6R)-HNK to investigate NMDAR inhibition.^{24, 25, 27} Furthermore, some studies showed that (2R, 6R)-HNK did not mediate the antidepressant effect of ketamine.^{19, 116} These contradicting results highlight the complicated and controversial roles of NMDARs in the anti-depressant effects of ketamine, and the underlying molecular mechanisms need to be further investigated. Nevertheless, the AMPAR upregulation, brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) signaling, and protein synthesis contributed to the anti-depressant effects of ketamine and its metabolite HNK (Figure 1).^{24, 25, 27, 78} Recently, it has been reported that the activation of NMDARs is required for the anti-depressant effects of ketamine and HNK.¹¹⁷ Therefore, the functions of the ketamine metabolite (2R, 6R)-HNK in NMDAR inhibition and its antidepressant effects are still controversial.^{19, 28} The ketamine metabolites (2R, 6R; 2S, 6S)-HNK did not produce anesthetic effects, which indicated that the anesthetic and antidepressant effects of ketamine were mediated by different metabolites. In line with this, both ketamine and its metabolite NK induced anesthetic effects.²¹ Moreover, if the dissociation side effects were not related to the antidepressant effects of ketamine,⁶⁵ and NMDAR inhibition might not have primarily contributed to these antidepressant effects of ketamine, which further complicated the molecular mechanisms underlying the anesthetic and antidepressant effects of ketamine.

Mechanistically, the activation of AMPARs, ERK–BDNF signaling, mTOR signaling, increased protein synthesis, and increased synaptic density contributed to the long-lasting antidepressant effects of ketamine.^{78, 118-121} Although both ERK and mTOR signaling regulated protein synthesis, the mTOR signaling might have mediated the antidepressant effects of (S-)-ketamine, and the antidepressant effects of (R-)-ketamine might have been mediated by ERK signaling (Figure 1).^{122, 123} Microglial transforming growth factor-beta1 was also essential for the antidepressant effects of (R-)-ketamine.¹²⁴ Given that the partial blockage of NMDARs by subanaesthetic doses of ketamine induces antidepressant effects, the different subunits of NMDARs may affect the antidepressant effects of ketamine. Accordingly, a previous study has shown that GluN2B selective NMDAR antagonists could induce antidepressant effects,¹²⁵ and that GluN2B-containing NMDARs mediated the antidepressant effects of ketamine.^{119, 126} Furthermore, the GluN2B in γ-aminobutyric acid (GABA)ergic interneurons, and not the glutamatergic neurons contributed to the antidepressant effects of ketamine,^{127, 128} which suggested that the partial blockage of NMDARs induced the antidepressant effects of ketamine.^128-131 Mechanistically, GluN2B-containing NMDAR inhibition by ketamine could activate mTORC1, and subsequently increase the synaptic protein synthesis and spine number, therefore producing rapid antidepressant effects.⁷⁸ However, small-scale human clinical trials showed that the mTOR inhibitor rapamycin did not block but rather enhanced the antidepressant effects of ketamine,¹³² which suggested that the molecular mechanistic explanation for the antidepressant effects of ketamine in humans and animals should be further investigated.

5.4 NMDAR-mediated excitatory/inhibitory balance contributed to the ketamine activity

Typically, primary ionotropic glutamate receptors such as NMDARs and AMPARs, in the glutamatergic excitatory pyramidal neurons generated excitatory synaptic transmissions, and the gamma-aminobutyric acid type A receptors (GABA_ARs) exhibit inhibitory synaptic transmission through GABAergic inhibitory interneurons.¹³³ The excitatory/inhibitory (E/I) balance is essential for the processing of cortical information.¹³⁴ The E/I imbalance has been a prominent hypothesis in psychiatric diseases, such as schizophrenia and autism.¹³⁵ Subanaesthetic doses of ketamine could be used to generate a pharmacological animal model of schizophrenia,^{136, 137} suggesting that the E/I balance is related to ketamine actions. However, interneurons comprise only 10%–15% of all cortical neurones in rodents, and are required for E/I balance and cortical functions.^{138, 139} Pyramidal neurones mediate excitatory synaptic transmission. The interneurons innervate almost every local pyramidal neurone and provide feedforward and feedback inhibition on the excitatory neurones.¹⁴⁰ Subanaesthetic doses of ketamine blocked the GluN2B-containing NMDARs in interneurons,¹²⁸ and then reduced the synaptic GABAergic inhibitory synaptic transmission, therefore resulting in the disinhibition of excitatory pyramidal neurons and producing the antidepressant effects.^{128, 141} Taken together, these studies demonstrated that the low dose of ketamine shifted the E/I balance towards excitation, thereby reducing the long-lasting antidepressant effects (Figure 2).

NMDARs can regulate the synaptic localization and functions of AMPARs and GABA_ARs,^{130, 142} thereby playing crucial roles in E/I balance.^{141, 143, 144} For more details about the roles of NMDARs in E/I balance, see a recent review.¹⁴⁵ Low doses of ketamine should also block NMDARs in excitatory pyramidal neurons. However, a decrease in excitatory input would reduce the inhibitory input onto a single pyramidal neuron, generating E/I balance in a cellular autonomous manner.^{146, 147} Reversely, the decrease in inhibitory input may not affect the excitatory input.^{146, 148, 149} Therefore, NMDAR inhibition using low doses of ketamine attenuated the inhibition of interneurons, resulting in E/I imbalance (Figure 2).¹⁵⁰

The development switch from GluN2B- to GluN2A-containing NMDARs in the synaptic regions and the higher mobility of GluN2B than of GluN2A in the extrasynaptic regions resulted in synaptic localized GluN2A-containing NMDARs and extrasynaptic localized GluN2B-containing NMDARs.^151-153 The postsynaptic density consisted of synaptic NMDARs and thousands of proteins,¹⁵⁴ and exhibited as a dense lamina under an electron microscope.¹⁵⁵ Therefore, a low dose of ketamine could not freely pass through the postsynaptic density, and could also not block the synaptic NMDARs. Therefore, a low dose of ketamine might only block the GluN2B-containing NMDARs in extra-synapses, and a high concentration of ketamine could block the GluN2A-containing NMDARs in synapses, and the GluN2B-containing NMDARs in extra-synapses (Figure 2). Accordingly, animal models of schizophrenia generated using subanaesthetic doses of ketamine,^{136, 137} and the hypofunction of NMDARs in interneurons could induce schizophrenia-relevant phenotypes.^{156, 157}

6 FUTURE PERSPECTIVES

The rapid onset and sustained anesthetic and antidepressant effects of ketamine were dose-dependent. S-ketamine induced rapid onset and sustained anesthetic effects without severe psychotomimetic side effects.^{158, 159} By contrast, R-ketamine generated rapid-onset and long-lasting antidepressant effects without abuse liability and side effects at a subanaesthetic dose.⁸² Therefore, S-ketamine might be used as an anesthetic at higher doses, whereas R-ketamine may exhibit antidepressant effects at lower doses.

Due to the rapid metabolism of ketamine into its downstream metabolites, it is proposed that these metabolites mediate the long-lasting effects of ketamine. NK could produce anesthetic effects, and HNK could induce antidepressant effects, although these studies were inconsistent and controversial.^{19, 24, 27} Furthermore, recent studies have shown that these pharmacological properties of the metabolites were significantly attenuated compared to those of unmetabolized ketamine.^{21, 28} Therefore, the metabolism of ketamine cannot substantiate the ketamine actions, or unmetabolized ketamine may be responsible for the anesthetic and antidepressant effects, all of which need further investigation.

As an NMDAR antagonist, the roles of NMDARs have been extensively studied in the anesthetic and antidepressant effects of ketamine. However, the roles of NMDARs in the antidepressant effects of ketamine are complicated and controversial. Furthermore, ketamine could also bind/affect other receptors, such as HCN1 channels,^{160, 161} σ1 receptor,¹⁶² dopamine,^{163, 164} and serotonin receptors,¹⁶⁵ although with a lower affinity compared with that of NMDARs, suggesting that other receptor systems might also mediate ketamine-mediated anesthetic and antidepressant effects. In line with this, HCN1 channels were found to mediate the hypnotic actions of ketamine,^{160, 161} and the dopamine receptors affected the antidepressant effects and abuse potential of ketamine.¹⁶³ Moreover, opioid receptors contributed to the antidepressant effects of ketamine.^{166, 167} Recent studies have suggested that opioid receptors might mediate the abuse potential of (S-)-ketamine.^{168, 169} Furthermore, the brain networks such as the connections between the frontal cortex and striatal system, the subgenual anterior cingulate cortex (sgACC), and the posterior cingulate cortex (PCC) system, were abnormal in depressed patients, and this may be restored using low doses of ketamine.¹⁷⁰ Therefore, investigating the subsequent effects of ketamine on the integrated nervous system would help eliminate side effects.

As the primary molecular targets of ketamine, NMDARs also mediate the analgesic and anti-inflammatory effects of ketamine, although the underlying molecular signaling pathways remain unclear. Furthermore, the severe side effects of ketamine and its abuse potential are mediated by ketamine-induced hypofunction of NMDARs.¹⁷¹ These would attenuate the clinical applications of anesthetics and antidepressants. Thus, the design and synthesis of neo-analogs of ketamine with mildly psychoactive effects and a lower abuse potential would benefit patients.

Besides their major ionotropic functions (Ca²⁺ influx), NMDARs also exhibit metabotropic functions, which are Ca²⁺ influx independent.¹⁷² The metabotropic functions of NMDARs contribute to long-term depression and the development switch of GluN2A- to GluN2B-containing NMDARs.^{173, 174} The contributions of the metabotropic functions of NMDARs to those of ketamine require further investigation.

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (32170975).

CONFLICT OF INTEREST STATEMENT

There were no conflicts of interest.

Open Research

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

REFERENCES

1Weiser TG, Regenbogen SE, Thompson KD, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet. 2008; 372(9633): 139-144.
10.1016/S0140-6736(08)60878-8
PubMed Web of Science® Google Scholar
2Schraag S, Pradelli L, Alsaleh AJO, et al. Propofol vs. inhalational agents to maintain general anaesthesia in ambulatory and in-patient surgery: a systematic review and meta-analysis. BMC Anesthesiol. 2018; 18(1): 162.
10.1186/s12871-018-0632-3
PubMed Web of Science® Google Scholar
3Petrenko AB, Yamakura T, Sakimura K, Baba H. Defining the role of NMDA receptors in anesthesia: are we there yet? Eur J Pharmacol. 2014; 723: 29-37.
10.1016/j.ejphar.2013.11.039
CAS PubMed Web of Science® Google Scholar
4Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. 2016; 10: 612.
10.3389/fnhum.2016.00612
PubMed Web of Science® Google Scholar
5Dilip TS, Chandy GM, Hazra D, Selvan J, Ganesan P. The adverse effects of ketamine on procedural sedation and analgesia (PSA) in the emergency department. J Family Med Prim Care. 2021; 10(6): 2279-2283.
10.4103/jfmpc.jfmpc_2140_20
CAS PubMed Google Scholar
6Acevedo-Diaz EE, Cavanaugh GW, Greenstein D, et al. Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression. J Affect Disord. 2020; 263: 568-575.
10.1016/j.jad.2019.11.028
CAS PubMed Web of Science® Google Scholar
7Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000; 47(4): 351-354.
10.1016/S0006-3223(99)00230-9
CAS PubMed Web of Science® Google Scholar
8Raffa RB, Pergolizzi JV Jr, Taylor R Jr, Group NR. The rapid-onset antidepressant effect of ketamine: more surprises? J Clin Pharm Ther. 2018; 43(2): 308-311.
10.1111/jcpt.12656
CAS PubMed Web of Science® Google Scholar
9Phillips JL, Norris S, Talbot J, et al. Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019; 176(5): 401-409.
10.1176/appi.ajp.2018.18070834
PubMed Web of Science® Google Scholar
10Ballard ED, Zarate CA Jr. The role of dissociation in ketamine's antidepressant effects. Nat Commun. 2020; 11(1): 6431.
10.1038/s41467-020-20190-4
CAS PubMed Web of Science® Google Scholar
11Penta JS, Rozencweig M, Guarino AM, Muggia FM. Mouse and large-animal toxicology studies of twelve antitumor agents: relevance to starting dose for phase I clinical trials. Cancer Chemother Pharmacol. 1979; 3(2): 97-101.
10.1007/BF00254979
CAS PubMed Web of Science® Google Scholar
12Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013; 19(6): 370-380.
10.1111/cns.12099
CAS PubMed Web of Science® Google Scholar
13Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018; 23(4): 801-811.
10.1038/mp.2017.255
CAS PubMed Web of Science® Google Scholar
14Daniell LC. The noncompetitive N-methyl-D-aspartate antagonists, MK-801, phencyclidine and ketamine, increase the potency of general anesthetics. Pharmacol Biochem Behav. 1990; 36(1): 111-115.
10.1016/0091-3057(90)90134-4
CAS PubMed Web of Science® Google Scholar
15Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol. 2013; 4: 161.
10.3389/fphar.2013.00161
PubMed Web of Science® Google Scholar
16Matveychuk D, Thomas RK, Swainson J, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020; 10:2045125320916657.
10.1177/2045125320916657
Web of Science® Google Scholar
17Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018; 70(3): 621-660.
10.1124/pr.117.015198
CAS PubMed Web of Science® Google Scholar
18Farmer CA, Gilbert JR, Moaddel R, et al. Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression. Neuropsychopharmacology. 2020; 45(8): 1398-1404.
10.1038/s41386-020-0663-6
CAS PubMed Web of Science® Google Scholar
19Yamaguchi JI, Toki H, Qu Y, et al. (2R,6R)-Hydroxynorketamine is not essential for the antidepressant actions of (R)-ketamine in mice. Neuropsychopharmacology. 2018; 43(9): 1900-1907.
10.1038/s41386-018-0084-y
CAS PubMed Web of Science® Google Scholar
20Sleigh J, Harvey M, Voss L, Denny B. Ketamine— more mechanisms of action than just NMDA blockade. Trends Anaesth Crit. 2014; 4(2–3): 76-81.
10.1016/j.tacc.2014.03.002
Google Scholar
21Leung LY, Baillie TA. Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. J Med Chem. 1986; 29(11): 2396-2399.
10.1021/jm00161a043
CAS PubMed Web of Science® Google Scholar
22Frenkel C, Urban BW. Molecular actions of racemic ketamine on human CNS sodium channels. Br J Anaesth. 1992; 69(3): 292-297.
10.1093/bja/69.3.292
CAS PubMed Web of Science® Google Scholar
23Wagner LE II, Gingrich KJ, Kulli JC, Yang J. Ketamine blockade of voltage-gated sodium channels: evidence for a shared receptor site with local anesthetics. Anesthesiology. 2001; 95(6): 1406-1413.
10.1097/00000542-200112000-00020
CAS PubMed Web of Science® Google Scholar
24Zanos P, Moaddel R, Morris PJ, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016; 533(7604): 481-486.
10.1038/nature17998
CAS PubMed Web of Science® Google Scholar
25Zanos P, Moaddel R, Morris PJ, et al. Zanos et al reply. Nature. 2017; 546(7659): E4-E5.
10.1038/nature22085
CAS PubMed Google Scholar
26Lumsden EW, Troppoli TA, Myers SJ, et al. Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function. Proc Natl Acad Sci U S A. 2019; 116(11): 5160-5169.
10.1073/pnas.1816071116
CAS PubMed Web of Science® Google Scholar
27Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM. Effects of a ketamine metabolite on synaptic NMDAR function. Nature. 2017; 546(7659): E1-E3.
10.1038/nature22084
CAS PubMed Web of Science® Google Scholar
28Yang C, Qu Y, Abe M, Nozawa D, Chaki S, Hashimoto K. (R)-ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry. 2017; 82(5): e43-e44.
10.1016/j.biopsych.2016.12.020
CAS PubMed Web of Science® Google Scholar
29Mion G. History of anaesthesia: the ketamine story – past, present and future. Eur J Anaesthesiol. 2017; 34(9): 571-575.
10.1097/EJA.0000000000000638
PubMed Web of Science® Google Scholar
30Ryu IS, Kim OH, Lee YE, et al. The abuse potential of novel synthetic phencyclidine derivative 1-(1-(4-fluorophenyl)cyclohexyl)piperidine (4'-F-PCP) in rodents. Int J Mol Sci. 2020; 21(13): 4631.
10.3390/ijms21134631
CAS PubMed Web of Science® Google Scholar
31Wallach J, Brandt SD. Phencyclidine-based new psychoactive substances. New Psychoactive Substances: Pharmacology, Clinical, Forensic and Analytical Toxicology. Front Chem. 2018; 252: 261-303.
CAS Google Scholar
32Pai A, Heining M. Ketamine. Continuing Education in Anaesth Crit Care Pain. 2007; 7(2): 59-63.
10.1093/bjaceaccp/mkm008
Google Scholar
33Ryder S, Way WL, Trevor AJ. Comparative pharmacology of the optical isomers of ketamine in mice. Eur J Pharmacol. 1978; 49(1): 15-23.
10.1016/0014-2999(78)90217-0
CAS PubMed Web of Science® Google Scholar
34Muller J, Pentyala S, Dilger J, Pentyala S. Ketamine enantiomers in the rapid and sustained antidepressant effects. Ther Adv Psychopharmacol. 2016; 6(3): 185-192.
10.1177/2045125316631267
CAS PubMed Web of Science® Google Scholar
35Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet. 2016; 55(9): 1059-1077.
10.1007/s40262-016-0383-6
CAS PubMed Web of Science® Google Scholar
36Chaki S. Beyond ketamine: new approaches to the development of safer antidepressants. Curr Neuropharmacol. 2017; 15(7): 963-976.
10.2174/1570159X15666170221101054
CAS PubMed Web of Science® Google Scholar
37Kamp J, Jonkman K, van Velzen M, et al. Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis. Br J Anaesth. 2020; 125(5): 750-761.
10.1016/j.bja.2020.06.067
CAS PubMed Web of Science® Google Scholar
38Zarate CA Jr, Brutsche N, Laje G, et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry. 2012; 72(4): 331-338.
10.1016/j.biopsych.2012.03.004
CAS PubMed Web of Science® Google Scholar
39Kurdi MS, Theerth KA, Deva RS. Ketamine: current applications in anesthesia, pain, and critical care. Anesth Essays Res. 2014; 8(3): 283-290.
10.4103/0259-1162.143110
PubMed Google Scholar
40Corssen G, Domino EF. Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative Cl-581. Anesth Analg. 1966; 45(1): 29-40.
10.1213/00000539-196601000-00007
CAS PubMed Web of Science® Google Scholar
41Domino EF, Chodoff P, Corssen G. Pharmacologic effects of ci-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965; 6: 279-291.
10.1002/cpt196563279
CAS PubMed Web of Science® Google Scholar
42Marland S, Ellerton J, Andolfatto G, et al. Ketamine: use in anesthesia. CNS Neurosci Ther. 2013; 19(6): 381-389.
10.1111/cns.12072
CAS PubMed Web of Science® Google Scholar
43Lee U, Ku S, Noh G, Baek S, Choi B, Mashour GA. Disruption of frontal-parietal communication by ketamine, propofol, and sevoflurane. Anesthesiology. 2013; 118(6): 1264-1275.
10.1097/ALN.0b013e31829103f5
CAS PubMed Web of Science® Google Scholar
44Schroeder KE, Irwin ZT, Gaidica M, et al. Disruption of corticocortical information transfer during ketamine anesthesia in the primate brain. Neuroimage. 2016; 134: 459-465.
10.1016/j.neuroimage.2016.04.039
CAS PubMed Web of Science® Google Scholar
45Li D, Vlisides PE, Mashour GA. Dynamic reconfiguration of frequency-specific cortical coactivation patterns during psychedelic and anesthetized states induced by ketamine. Neuroimage. 2022; 249:118891.
10.1016/j.neuroimage.2022.118891
CAS PubMed Web of Science® Google Scholar
46Dai R, Larkin TE, Huang Z, et al. Classical and non-classical psychedelic drugs induce common network changes in human cortex. Neuroimage. 2023; 273:120097.
10.1016/j.neuroimage.2023.120097
PubMed Web of Science® Google Scholar
47Jansen KL, Darracot-Cankovic R. The nonmedical use of ketamine, part two: a review of problem use and dependence. J Psychoactive Drugs. 2001; 33(2): 151-158.
10.1080/02791072.2001.10400480
CAS PubMed Web of Science® Google Scholar
48Highland JN, Zanos P, Riggs LM, et al. Hydroxynorketamines: pharmacology and potential therapeutic applications. Pharmacol Rev. 2021; 73(2): 763-791.
10.1124/pharmrev.120.000149
CAS PubMed Web of Science® Google Scholar
49Abbott JA, Popescu GK. Hydroxynorketamine blocks N-methyl-d-aspartate receptor currents by binding to closed receptors. Mol Pharmacol. 2020; 98(3): 203-210.
10.1124/mol.120.119784
CAS PubMed Web of Science® Google Scholar
50Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999; 283(5398): 70-74.
10.1126/science.283.5398.70
CAS PubMed Web of Science® Google Scholar
51Hayashi H, Dikkes P, Soriano SG. Repeated administration of ketamine may lead to neuronal degeneration in the developing rat brain. Paediatr Anaesth. 2002; 12(9): 770-774.
10.1046/j.1460-9592.2002.00883.x
CAS PubMed Web of Science® Google Scholar
52Paule MG, Li M, Allen RR, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011; 33(2): 220-230.
10.1016/j.ntt.2011.01.001
CAS PubMed Web of Science® Google Scholar
53Wang C, Sadovova N, Hotchkiss C, et al. Blockade of N-methyl-D-aspartate receptors by ketamine produces loss of postnatal day 3 monkey frontal cortical neurons in culture. Toxicol Sci. 2006; 91(1): 192-201.
10.1093/toxsci/kfj144
CAS PubMed Web of Science® Google Scholar
54McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021; 178(5): 383-399.
10.1176/appi.ajp.2020.20081251
PubMed Web of Science® Google Scholar
55Grady SE, Marsh TA, Tenhouse A, Klein K. Ketamine for the treatment of major depressive disorder and bipolar depression: a review of the literature. Ment Health Clin. 2017; 7(1): 16-23.
10.9740/mhc.2017.01.016
PubMed Google Scholar
56Jenkins E, Goldner EM. Approaches to understanding and addressing treatment-resistant depression: a scoping review. Depress Res Treat 2012; 2012: 1-7.
10.1155/2012/469680
Google Scholar
57Leal GC, Bandeira ID, Correia-Melo FS, et al. Intravenous arketamine for treatment-resistant depression: open-label pilot study. Eur Arch Psychiatry Clin Neurosci. 2021; 271(3): 577-582.
10.1007/s00406-020-01110-5
PubMed Web of Science® Google Scholar
58Bandeira ID, Leal GC, Correia-Melo FS, et al. Arketamine for bipolar depression: Open-label, dose-escalation, pilot study. J Psychiatr Res. 2023; 164: 229-234.
10.1016/j.jpsychires.2023.06.028
PubMed Google Scholar
59Aan Het Rot M, Zarate CA Jr, Charney DS, Mathew SJ. Ketamine for depression: where do we go from here? Biol Psychiatry. 2012; 72(7): 537-547.
10.1016/j.biopsych.2012.05.003
CAS PubMed Web of Science® Google Scholar
60Xu J, Lei H. Ketamine-an update on its clinical uses and abuses. CNS Neurosci Ther. 2014; 20(12): 1015-1020.
10.1111/cns.12363
CAS PubMed Web of Science® Google Scholar
61Mkrtchian A, Evans JW, Kraus C, et al. Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals. Mol Psychiatry. 2021; 26(7): 3292-3301.
10.1038/s41380-020-00878-1
CAS PubMed Web of Science® Google Scholar
62Chen MH, Chang WC, Lin WC, et al. Functional dysconnectivity of frontal cortex to striatum predicts ketamine infusion response in treatment-resistant depression. Int J Neuropsychopharmacol. 2020; 23(12): 791-798.
10.1093/ijnp/pyaa056
CAS PubMed Web of Science® Google Scholar
63Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010; 67(8): 793-802.
10.1001/archgenpsychiatry.2010.90
CAS PubMed Web of Science® Google Scholar
64Luckenbaugh DA, Niciu MJ, Ionescu DF, et al. Do the dissociative side effects of ketamine mediate its antidepressant effects? J Affect Disord. 2014; 159: 56-61.
10.1016/j.jad.2014.02.017
CAS PubMed Web of Science® Google Scholar
65Chen G, Chen L, Zhang Y, et al. Relationship between dissociation and antidepressant effects of Esketamine nasal spray in patients with treatment-resistant depression. Int J Neuropsychopharmacol. 2022; 25(4): 269-279.
10.1093/ijnp/pyab084
CAS PubMed Web of Science® Google Scholar
66Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63(8): 856-864.
10.1001/archpsyc.63.8.856
CAS PubMed Web of Science® Google Scholar
67Clements JA, Nimmo WS, Grant IS. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982; 71(5): 539-542.
10.1002/jps.2600710516
CAS PubMed Web of Science® Google Scholar
68Schuttler J, Stanski DR, White PF, et al. Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. J Pharmacokinet Biopharm. 1987; 15(3): 241-253.
10.1007/BF01066320
CAS PubMed Google Scholar
69Domino EF, Domino SE, Smith RE, et al. Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther. 1984; 36(5): 645-653.
10.1038/clpt.1984.235
CAS PubMed Web of Science® Google Scholar
70Fava M, Freeman MP, Flynn M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020; 25(7): 1592-1603.
10.1038/s41380-018-0256-5
CAS PubMed Web of Science® Google Scholar
71Schwartz J, Murrough JW, Iosifescu DV. Ketamine for treatment-resistant depression: recent developments and clinical applications. Evid Based Ment Health. 2016; 19(2): 35-38.
10.1136/eb-2016-102355
PubMed Web of Science® Google Scholar
72Autry AE, Adachi M, Nosyreva E, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011; 475(7354): 91-95.
10.1038/nature10130
CAS PubMed Web of Science® Google Scholar
73Maj J, Rogoz Z, Skuza G, Sowinska H. Effects of MK-801 and antidepressant drugs in the forced swimming test in rats. Eur Neuropsychopharmacol. 1992; 2(1): 37-41.
10.1016/0924-977X(92)90034-6
CAS PubMed Google Scholar
74Serafini G, Pompili M, Innamorati M, Dwivedi Y, Brahmachari G, Girardi P. Pharmacological properties of glutamatergic drugs targeting NMDA receptors and their application in major depression. Curr Pharm des. 2013; 19(10): 1898-1922.
10.2174/13816128113199990293
CAS PubMed Web of Science® Google Scholar
75Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015; 172(10): 950-966.
10.1176/appi.ajp.2015.15040465
PubMed Web of Science® Google Scholar
76Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016; 46(7): 1459-1472.
10.1017/S0033291716000064
CAS PubMed Web of Science® Google Scholar
77Ates-Alagoz Z, Adejare A. NMDA receptor antagonists for treatment of depression. Pharmaceuticals (Basel). 2013; 6(4): 480-499.
10.3390/ph6040480
CAS PubMed Google Scholar
78Li N, Lee B, Liu RJ, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010; 329(5994): 959-964.
10.1126/science.1190287
CAS PubMed Web of Science® Google Scholar
79Dravid SM, Erreger K, Yuan H, et al. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block. J Physiol. 2007; 581(Pt 1): 107-128.
10.1113/jphysiol.2006.124958
CAS PubMed Web of Science® Google Scholar
80Kotermanski SE, Wood JT, Johnson JW. Memantine binding to a superficial site on NMDA receptors contributes to partial trapping. J Physiol. 2009; 587(Pt 19): 4589-4604.
10.1113/jphysiol.2009.176297
CAS PubMed Web of Science® Google Scholar
81Domino EF. Taming the ketamine tiger. 1965. Anesthesiology. 2010; 113(3): 678-684.
10.1097/ALN.0b013e3181ed09a2
PubMed Web of Science® Google Scholar
82Yang C, Shirayama Y, Zhang JC, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry. 2015; 5(9):e632.
10.1038/tp.2015.136
CAS PubMed Web of Science® Google Scholar
83Paul R, Schaaff N, Padberg F, Moller HJ, Frodl T. Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: report of two cases. World J Biol Psychiatry. 2009; 10(3): 241-244.
10.1080/15622970701714370
PubMed Web of Science® Google Scholar
84Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci. 2011; 33(8): 1351-1365.
10.1111/j.1460-9568.2011.07628.x
PubMed Web of Science® Google Scholar
85Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013; 14(6): 383-400.
10.1038/nrn3504
CAS PubMed Web of Science® Google Scholar
86Brothwell SLC, Barber JL, Monaghan DT, Jane DE, Gibb AJ, Jones S. NR2B- and NR2D-containing synaptic NMDA receptors in developing rat substantia nigra pars compacta dopaminergic neurones. J Physiol. 2008; 586(3): 739-750.
10.1113/jphysiol.2007.144618
CAS PubMed Web of Science® Google Scholar
87Shipton OA, Paulsen O. GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans R Soc Lond B Biol Sci. 2014; 369(1633):20130163.
10.1098/rstb.2013.0163
PubMed Web of Science® Google Scholar
88Holehonnur R, Phensy AJ, Kim LJ, et al. Increasing the GluN2A/GluN2B ratio in neurons of the mouse basal and lateral amygdala inhibits the modification of an existing fear memory trace. J Neurosci. 2016; 36(36): 9490-9504.
10.1523/JNEUROSCI.1743-16.2016
CAS PubMed Web of Science® Google Scholar
89Lu W, Du J, Goehring A, Gouaux E. Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation. Science. 2017; 355(6331):eaal3729.
10.1126/science.aal3729
PubMed Web of Science® Google Scholar
90Rajani V, Sengar AS, Salter MW. Tripartite signalling by NMDA receptors. Mol Brain. 2020; 13(1): 23.
10.1186/s13041-020-0563-z
CAS PubMed Web of Science® Google Scholar
91Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984; 307(5950): 462-465.
10.1038/307462a0
CAS PubMed Web of Science® Google Scholar
92Lau CG, Takeuchi K, Rodenas-Ruano A, et al. Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans. 2009; 37(Pt 6): 1369-1374.
10.1042/BST0371369
CAS PubMed Web of Science® Google Scholar
93Guo H, Camargo LM, Yeboah F, et al. A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine. Sci Rep. 2017; 7(1):11608.
10.1038/s41598-017-11947-x
PubMed Google Scholar
94Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci. 2010; 11(10): 682-696.
10.1038/nrn2911
CAS PubMed Web of Science® Google Scholar
95Zhu S, Stein RA, Yoshioka C, et al. Mechanism of NMDA receptor inhibition and activation. Cell. 2016; 165(3): 704-714.
10.1016/j.cell.2016.03.028
CAS PubMed Web of Science® Google Scholar
96MacDonald JF, Miljkovic Z, Pennefather P. Use-dependent block of excitatory amino acid currents in cultured neurons by ketamine. J Neurophysiol. 1987; 58(2): 251-266.
10.1152/jn.1987.58.2.251
CAS PubMed Web of Science® Google Scholar
97Singh NS, Zarate CA Jr, Moaddel R, Bernier M, Wainer IW. What is hydroxynorketamine and what can it bring to neurotherapeutics? Expert Rev Neurother. 2014; 14(11): 1239-1242.
10.1586/14737175.2014.971760
CAS PubMed Web of Science® Google Scholar
98Holtman JR Jr, Crooks PA, Johnson-Hardy JK, Hojomat M, Kleven M, Wala EP. Effects of norketamine enantiomers in rodent models of persistent pain. Pharmacol Biochem Behav. 2008; 90(4): 676-685.
10.1016/j.pbb.2008.05.011
CAS PubMed Web of Science® Google Scholar
99Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol. 1997; 333(1): 99-104.
10.1016/S0014-2999(97)01116-3
CAS PubMed Web of Science® Google Scholar
100Dickinson R, Peterson BK, Banks P, et al. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor by the anesthetics xenon and isoflurane: evidence from molecular modeling and electrophysiology. Anesthesiology. 2007; 107(5): 756-767.
10.1097/01.anes.0000287061.77674.71
CAS PubMed Web of Science® Google Scholar
101Yamakura T, Harris RA. Effects of gaseous anesthetics nitrous oxide and xenon on ligand-gated ion channels. Comparison with isoflurane and ethanol. Anesthesiology. 2000; 93(4): 1095-1101.
10.1097/00000542-200010000-00034
CAS PubMed Web of Science® Google Scholar
102Franks NP, Dickinson R, de Sousa SLM, Hall AC, Lieb WR. How does xenon produce anaesthesia? Nature. 1998; 396(6709): 324.
10.1038/24525
CAS PubMed Web of Science® Google Scholar
103Yamakura T, Askalany AR, Petrenko AB, Kohno T, Baba H, Sakimura K. The NR3B subunit does not alter the anesthetic sensitivities of recombinant N-methyl-D-aspartate receptors. Anesth Analg. 2005; 100(6): 1687-1692.
10.1213/01.ANE.0000152324.30272.49
CAS PubMed Web of Science® Google Scholar
104Franks NP. Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006; 147(Suppl 1): S72-S81.
10.1038/sj.bjp.0706441
CAS PubMed Web of Science® Google Scholar
105Petrenko AB, Yamakura T, Fujiwara N, Askalany AR, Baba H, Sakimura K. Reduced sensitivity to ketamine and pentobarbital in mice lacking the N-methyl-D-aspartate receptor GluRepsilon1 subunit. Anesth Analg. 2004; 99(4): 1136-1140.
10.1213/01.ANE.0000131729.54986.30
CAS PubMed Web of Science® Google Scholar
106Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010; 30(17): 5866-5875.
10.1523/JNEUROSCI.0167-10.2010
CAS PubMed Web of Science® Google Scholar
107Mikasova L, De Rossi P, Bouchet D, et al. Disrupted surface cross-talk between NMDA and ephrin-B2 receptors in anti-NMDA encephalitis. Brain. 2012; 135(5): 1606-1621.
10.1093/brain/aws092
PubMed Web of Science® Google Scholar
108Huang YQ, Xiong H. Anti-NMDA receptor encephalitis: a review of mechanistic studies. Int J Physiol Pathophysiol Pharmacol. 2021; 13(1): 1-11.
PubMed Google Scholar
109Kawano H, Hamaguchi E, Kawahito S, et al. Anaesthesia for a patient with paraneoplastic limbic encephalitis with ovarian teratoma: relationship to anti-N-methyl-d-aspartate receptor antibodies. Anaesthesia. 2011; 66(6): 515-518.
10.1111/j.1365-2044.2011.06707.x
CAS PubMed Web of Science® Google Scholar
110Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33(1): 70-75.
10.1016/j.pnpbp.2008.10.005
CAS PubMed Web of Science® Google Scholar
111Lorigooini Z, Salimi N, Soltani A, Amini-Khoei H. Implication of NMDA-NO pathway in the antidepressant-like effect of ellagic acid in male mice. Neuropeptides. 2019; 76:101928.
10.1016/j.npep.2019.04.003
CAS PubMed Web of Science® Google Scholar
112Sałat K, Siwek A, Starowicz G, et al. Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: role of activity at NMDA receptor. Neuropharmacology. 2015; 99: 301-307.
10.1016/j.neuropharm.2015.07.037
CAS PubMed Web of Science® Google Scholar
113Moaddel R, Abdrakhmanova G, Kozak J, et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in alpha7 nicotinic acetylcholine receptors. Eur J Pharmacol. 2013; 698(1–3): 228-234.
10.1016/j.ejphar.2012.11.023
CAS PubMed Web of Science® Google Scholar
114Hashimoto K. Ketamine's antidepressant action: beyond NMDA receptor inhibition. Expert Opin Ther Targets. 2016; 20(11): 1389-1392.
10.1080/14728222.2016.1238899
CAS PubMed Web of Science® Google Scholar
115Strekalova T, Spanagel R, Dolgov O, Bartsch D. Stress-induced hyperlocomotion as a confounding factor in anxiety and depression models in mice. Behav Pharmacol. 2005; 16(3): 171-180.
10.1097/00008877-200505000-00006
CAS PubMed Web of Science® Google Scholar
116Shirayama Y, Hashimoto K. Lack of antidepressant effects of (2R,6R)-Hydroxynorketamine in a rat learned helplessness model: comparison with (R)-ketamine. Int J Neuropsychopharmacol. 2018; 21(1): 84-88.
10.1093/ijnp/pyx108
CAS PubMed Web of Science® Google Scholar
117Zanos P, Brown KA, Georgiou P, et al. NMDA receptor activation-dependent antidepressant-relevant behavioral and synaptic actions of ketamine. J Neurosci. 2023; 43(6): 1038-1050.
10.1523/JNEUROSCI.1316-22.2022
CAS PubMed Web of Science® Google Scholar
118Holmes SE, Finnema SJ, Naganawa M, et al. Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Mol Psychiatry. 2022; 27(4): 2273-2281.
10.1038/s41380-022-01465-2
CAS PubMed Web of Science® Google Scholar
119Maeng S, Zarate CA Jr, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008; 63(4): 349-352.
10.1016/j.biopsych.2007.05.028
CAS PubMed Web of Science® Google Scholar
120Moda-Sava RN, Murdock MH, Parekh PK, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019; 364(6436): 1-12.
10.1126/science.aat8078
Web of Science® Google Scholar
121Kang MJY, Hawken E, Vazquez GH. The mechanisms behind rapid antidepressant effects of ketamine: a systematic review with a focus on molecular neuroplasticity. Front Psych. 2022; 13:860882.
10.3389/fpsyt.2022.860882
Google Scholar
122Yao W, Cao Q, Luo S, et al. Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine. Mol Psychiatry. 2022; 27(3): 1618-1629.
10.1038/s41380-021-01377-7
CAS PubMed Web of Science® Google Scholar
123Yang C, Ren Q, Qu Y, et al. Mechanistic target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry. 2018; 83(1): 18-28.
10.1016/j.biopsych.2017.05.016
CAS PubMed Web of Science® Google Scholar
124Zhang K, Yang C, Chang L, et al. Essential role of microglial transforming growth factor-β1 in antidepressant actions of (R)-ketamine and the novel antidepressant TGF-β1. Transl Psychiatry. 2020; 10(1): 32.
10.1038/s41398-020-0733-x
CAS PubMed Web of Science® Google Scholar
125Preskorn SH, Baker B, Kolluri S, Menniti FS, Krams M, Landen JW. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol. 2008; 28(6): 631-637.
10.1097/JCP.0b013e31818a6cea
CAS PubMed Web of Science® Google Scholar
126Lv S, Yao K, Zhang Y, Zhu S. NMDA receptors as therapeutic targets for depression treatment: evidence from clinical to basic research. Neuropharmacology. 2023; 225:109378.
10.1016/j.neuropharm.2022.109378
CAS PubMed Web of Science® Google Scholar
127Miller OH, Yang L, Wang C-C, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife. 2014; 3:e03581.
10.7554/eLife.03581
PubMed Web of Science® Google Scholar
128Gerhard DM, Pothula S, Liu R-J, et al. GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. J Clin Investig. 2020; 130(3): 1336-1349.
10.1172/JCI130808
CAS PubMed Web of Science® Google Scholar
129Hirota K, Lambert DG. Ketamine: new uses for an old drug? Br J Anaesth. 2011; 107(2): 123-126.
10.1093/bja/aer221
CAS PubMed Web of Science® Google Scholar
130Su T, Lu Y, Geng Y, Lu W, Chen Y. How could N-methyl-D-aspartate receptor antagonists lead to excitation instead of inhibition? Brain Sci Adv. 2019; 4(2): 73-98.
10.26599/BSA.2018.2018.9050009
Google Scholar
131Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997; 17(8): 2921-2927.
10.1523/JNEUROSCI.17-08-02921.1997
CAS PubMed Web of Science® Google Scholar
132Abdallah CG, Averill LA, Gueorguieva R, et al. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology. 2020; 45(6): 990-997.
10.1038/s41386-020-0644-9
CAS PubMed Web of Science® Google Scholar
133Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa JL. GABAA, NMDA and AMPA receptors: a developmentally regulated 'menage a trois'. Trends Neurosci. 1997; 20(11): 523-529.
10.1016/S0166-2236(97)01147-8
CAS PubMed Web of Science® Google Scholar
134Zhou S, Yu Y. Synaptic E-I balance underlies efficient neural coding. Front Neurosci. 2018; 12: 46.
10.3389/fnins.2018.00046
PubMed Web of Science® Google Scholar
135Sohal VS, Rubenstein JLR. Excitation-inhibition balance as a framework for investigating mechanisms in neuropsychiatric disorders. Mol Psychiatry. 2019; 24(9): 1248-1257.
10.1038/s41380-019-0426-0
PubMed Web of Science® Google Scholar
136Frohlich J, van Horn JD. Reviewing the ketamine model for schizophrenia. J Psychopharmacol. 2014; 28(4): 287-302.
10.1177/0269881113512909
CAS PubMed Web of Science® Google Scholar
137Abram SV, Roach BJ, Fryer SL, et al. Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia. Mol Psychiatry. 2022; 27(5): 2448-2456.
10.1038/s41380-022-01502-0
CAS PubMed Web of Science® Google Scholar
138Meyer HS, Schwarz D, Wimmer VC, et al. Inhibitory interneurons in a cortical column form hot zones of inhibition in layers 2 and 5A. Proc Natl Acad Sci U S A. 2011; 108(40): 16807-16812.
10.1073/pnas.1113648108
CAS PubMed Web of Science® Google Scholar
139Tremblay R, Lee S, Rudy B. GABAergic interneurons in the neocortex: from cellular properties to circuits. Neuron. 2016; 91(2): 260-292.
10.1016/j.neuron.2016.06.033
CAS PubMed Web of Science® Google Scholar
140Tepper JM, Wilson CJ, Koos T. Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons. Brain Res Rev. 2008; 58(2): 272-281.
10.1016/j.brainresrev.2007.10.008
CAS PubMed Google Scholar
141Widman AJ, McMahon LL. Disinhibition of CA1 pyramidal cells by low-dose ketamine and other antagonists with rapid antidepressant efficacy. Proc Natl Acad Sci U S A. 2018; 115(13): E3007-E3016.
10.1073/pnas.1718883115
CAS PubMed Web of Science® Google Scholar
142Ferreira JS, Schmidt J, Rio P, et al. GluN2B-containing NMDA receptors regulate AMPA receptor traffic through anchoring of the synaptic proteasome. J Neurosci. 2015; 35(22): 8462-8479.
10.1523/JNEUROSCI.3567-14.2015
CAS PubMed Web of Science® Google Scholar
143Kehrer C, Maziashvili N, Dugladze T, Gloveli T. Altered excitatory-inhibitory balance in the NMDA-hypofunction model of schizophrenia. Front Mol Neurosci. 2008; 1(6): 6.
PubMed Google Scholar
144Gupta SC, Ravikrishnan A, Liu J, et al. The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function. Sci Rep. 2016; 6(1):38321.
10.1038/srep38321
CAS PubMed Google Scholar
145Zhou L, Sun X, Duan J. NMDARs regulate the excitatory-inhibitory balance within neural circuits. Brain Sci Adv. 2023; 9(1): 3-14.
10.26599/BSA.2022.9050020
Google Scholar
146He H-y, Shen W, Zheng L, Guo X, Cline HT. Excitatory synaptic dysfunction cell-autonomously decreases inhibitory inputs and disrupts structural and functional plasticity. Nat Commun. 2018; 9(1): 2893.
10.1038/s41467-018-05125-4
PubMed Web of Science® Google Scholar
147Xue M, Atallah BV, Scanziani M. Equalizing excitation–inhibition ratios across visual cortical neurons. Nature. 2014; 511(7511): 596-600.
10.1038/nature13321
CAS PubMed Web of Science® Google Scholar
148Shen W, McKeown CR, Demas JA, Cline HT. Inhibition to excitation ratio regulates visual system responses and behavior in vivo. J Neurophysiol. 2011; 106(5): 2285-2302.
10.1152/jn.00641.2011
CAS PubMed Web of Science® Google Scholar
149Gu X, Zhou L, Lu W. An NMDA receptor-dependent mechanism underlies inhibitory synapse development. Cell Rep. 2016; 14(3): 471-478.
10.1016/j.celrep.2015.12.061
CAS PubMed Web of Science® Google Scholar
150Cichon J, Wasilczuk AZ, Looger LL, Contreras D, Kelz MB, Proekt A. Ketamine triggers a switch in excitatory neuronal activity across neocortex. Nat Neurosci. 2023; 26(1): 39-52.
10.1038/s41593-022-01203-5
CAS PubMed Web of Science® Google Scholar
151Groc L, Heine M, Cousins SL, et al. NMDA receptor surface mobility depends on NR2A-2B subunits. Proc Natl Acad Sci U S A. 2006; 103(49): 18769-18774.
10.1073/pnas.0605238103
CAS PubMed Web of Science® Google Scholar
152Tovar KR, Westbrook GL. Mobile NMDA receptors at hippocampal synapses. Neuron. 2002; 34(2): 255-264.
10.1016/S0896-6273(02)00658-X
CAS PubMed Web of Science® Google Scholar
153Zhang XM, Luo JH. GluN2A versus GluN2B: twins, but quite different. Neurosci Bull. 2013; 29(6): 761-772.
10.1007/s12264-013-1336-9
PubMed Web of Science® Google Scholar
154Kaizuka T, Takumi T. Postsynaptic density proteins and their involvement in neurodevelopmental disorders. J Biochem. 2018; 163(6): 447-455.
10.1093/jb/mvy022
CAS PubMed Web of Science® Google Scholar
155Dosemeci A, Weinberg RJ, Reese TS, Tao-Cheng JH. The postsynaptic density: there is more than meets the eye. Front Synaptic Neurosci. 2016; 8: 23.
10.3389/fnsyn.2016.00023
PubMed Google Scholar
156Cohen SM, Tsien RW, Goff DC, Halassa MM. The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr Res. 2015; 167(1–3): 98-107.
10.1016/j.schres.2014.12.026
PubMed Web of Science® Google Scholar
157Bygrave AM, Kilonzo K, Kullmann DM, Bannerman DM, Katzel D. Can N-methyl-D-aspartate receptor hypofunction in schizophrenia be localized to an individual cell type? Front Psych. 2019; 10: 835.
10.3389/fpsyt.2019.00835
PubMed Google Scholar
158Trimmel H, Helbok R, Staudinger T, et al. S(+)-ketamine: current trends in emergency and intensive care medicine. Wien Klin Wochenschr. 2018; 130(9–10): 356-366.
10.1007/s00508-017-1299-3
CAS PubMed Web of Science® Google Scholar
159Persson J. Wherefore ketamine? Curr Opin Anaesthesiol. 2010; 23(4): 455-460.
10.1097/ACO.0b013e32833b49b3
PubMed Web of Science® Google Scholar
160Chen X, Shu S, Bayliss DA. HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. J Neurosci. 2009; 29(3): 600-609.
10.1523/JNEUROSCI.3481-08.2009
CAS PubMed Web of Science® Google Scholar
161Zhou C, Douglas JE, Kumar NN, Shu S, Bayliss DA, Chen X. Forebrain HCN1 channels contribute to hypnotic actions of ketamine. Anesthesiology. 2013; 118(4): 785-795.
10.1097/ALN.0b013e318287b7c8
CAS PubMed Web of Science® Google Scholar
162Hustveit O, Maurset A, Oye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol. 1995; 77(6): 355-359.
10.1111/j.1600-0773.1995.tb01041.x
CAS PubMed Web of Science® Google Scholar
163Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry. 2018; 23(1): 59-69.
10.1038/mp.2017.190
CAS PubMed Web of Science® Google Scholar
164Can A, Zanos P, Moaddel R, et al. Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters. J Pharmacol Exp Ther. 2016; 359(1): 159-170.
10.1124/jpet.116.235838
CAS PubMed Web of Science® Google Scholar
165Tiger M, Veldman ER, Ekman CJ, Halldin C, Svenningsson P, Lundberg J. A randomized placebo-controlled PET study of ketamine s effect on serotonin(1B) receptor binding in patients with SSRI-resistant depression. Transl Psychiatry. 2020; 10(1): 159.
10.1038/s41398-020-0844-4
CAS PubMed Web of Science® Google Scholar
166Klein ME, Chandra J, Sheriff S, Malinow R. Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents. Proc Natl Acad Sci U S A. 2020; 117(5): 2656-2662.
10.1073/pnas.1916570117
CAS PubMed Web of Science® Google Scholar
167Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine by opioid receptor antagonism. Am J Psychiatry. 2018; 175(12): 1205-1215.
10.1176/appi.ajp.2018.18020138
PubMed Web of Science® Google Scholar
168Bonaventura J, Lam S, Carlton M, et al. Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry. 2021; 26(11): 6704-6722.
10.1038/s41380-021-01093-2
CAS PubMed Web of Science® Google Scholar
169Levinstein MR, Carlton ML, di Ianni T, et al. Mu opioid receptor activation mediates (S)-ketamine reinforcement in rats: implications for abuse liability. Biol Psychiatry. 2023; 93(12): 1118-1126.
10.1016/j.biopsych.2022.12.019
CAS PubMed Web of Science® Google Scholar
170Ionescu DF, Felicione JM, Gosai A, et al. Ketamine-associated brain changes: a review of the neuroimaging literature. Harv Rev Psychiatry. 2018; 26(6): 320-339.
10.1097/HRP.0000000000000179
PubMed Web of Science® Google Scholar
171Newcomer JW, Farber NB, Jevtovic-Todorovic V, et al. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999; 20(2): 106-118.
10.1016/S0893-133X(98)00067-0
CAS PubMed Web of Science® Google Scholar
172Dore K, Stein IS, Brock JA, Castillo PE, Zito K, Sjostrom PJ. Unconventional NMDA receptor signaling. J Neurosci. 2017; 37(45): 10800-10807.
10.1523/JNEUROSCI.1825-17.2017
CAS PubMed Web of Science® Google Scholar
173Nabavi S, Kessels HW, Alfonso S, Aow J, Fox R, Malinow R. Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc Natl Acad Sci U S A. 2013; 110(10): 4027-4032.
10.1073/pnas.1219454110
CAS PubMed Web of Science® Google Scholar
174Kessels HW, Nabavi S, Malinow R. Metabotropic NMDA receptor function is required for beta-amyloid-induced synaptic depression. Proc Natl Acad Sci U S A. 2013; 110(10): 4033-4038.
10.1073/pnas.1219605110
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume30, Issue4

April 2024

e14464

The role of NMDARs in the anesthetic and antidepressant effects of ketamine