Ketamine a dissociative anesthetic: Neurobiology and biomolecular exploration in depression

Journal Pre-proof Ketamine a dissociative anesthetic: Neurobiology and biomolecular exploration in depression Guo-liang Liu, Yun-feng Cui, Chang Lu, Peng Zhao PII:

S0009-2797(20)30070-3

DOI:

https://doi.org/10.1016/j.cbi.2020.109006

Reference:

CBI 109006

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Chemico-Biological Interactions

Received Date: 15 January 2020 Revised Date:

7 February 2020

Accepted Date: 17 February 2020

Please cite this article as: G.-l. Liu, Y.-f. Cui, C. Lu, P. Zhao, Ketamine a dissociative anesthetic: Neurobiology and biomolecular exploration in depression, Chemico-Biological Interactions (2020), doi: https://doi.org/10.1016/j.cbi.2020.109006. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

Ketamine a Dissociative Anesthetic: Neurobiology and Biomolecular Exploration in Depression Guo-liang Liu1，Yun-feng Cui1，Chang Lu1，Peng Zhao1* 1. Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, Jilin, China *Corresponding Author: Peng ZHAO, Department of Anesthesiology, The Second Hospital of Jilin University, address: No 218 Ziqiang Street, Changchun 130041, Jilin, People’s Republic of China. Email id: [email protected]

Abstract Ketamine is gaining ground as a potential treating depression because it has a distinct mode of action than typical drugs that influence monoamine neurotransmitters including noradrenaline, dopamine, or serotonin. Ketamine is thought to act by blocking N-methyl-d-aspartate (NMDA) receptors in the brain, which interact with the amino acid neurotransmitter glutamate. The resultant chemical changes in the brain caused by ketamine are not yet fully understood but could involve ketamine-induced gene expression and signaling cascades that act long after the drug has been eliminated from the body. Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects including the emergence reactions (hallucinations, dreams, and out-of-body experiences) by recreational users, who need further study before longterm use of ketamine can be approved for depression. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels. Thus, we are exploring

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the involvement of molecular targets for the treatment and psychomimetic phenomena of the ketamine. Keywords: N-methyl D-Aspartate Receptor; ∆(9)-tetrahydrocannabinol, mitogen-activated protein kinase; endocannabinoid system, brain-derived neurotrophic factor; histone deacetylase 5.

1. Introduction Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine’s effects on the central nervous system remain incompletely understood. Ketamine is an arylcycloalkylamine that is structurally related to phencyclidine (PCP).

Ketamine produces an unusual state, sometimes referred to as

“dissociative anesthesia”, during this dissociative state, patients might appear awake with preserved airway reflexes and respiratory drive, but they are unable to respond to sensory input [1, 2]. The primary site of ketamine's central nervous system activity appears to be the thalamocortical projection system, where it causes depression of certain cortical and thalamic functions and stimulation of parts of the limbic system [3-5]. To date, not a single rapid-acting antidepressant (RAAD) or glutamate-based antipsychotic has been approved to treat depression or schizophrenia, although two decades have passed since the RAAD and psychotomimetic effects of ketamine were first reported in the 1990s [6, 7]. A major obstacle in this field is the lack of biomarkers that directly reflect synaptic glutamate neurotransmission. Such markers would serve to (1) test ketamine’s RAAD and 2

psychotomimetic mechanisms in humans and (2) permit expedited screening and optimization of putative novel glutamate-based RAAD and antipsychotic agents.

2. Neurobiology of ketamine Therapeutic medications for the treatment of depression have serious limitations, particularly delayed onset and low rates of efficacy. Early studies demonstrated that typical antidepressants altered the affinity of the NMDA receptor glycine site, suggesting the possibility that decreased NMDA receptor function contributes to antidepressant response. This hypothesis was directly tested first by Krystal, Berman, Charney, and colleagues at Yale when they investigated a single subanesthetic dose (0.5 mg/kg, intravenous [IV] infusion over the course of 40 minutes) of ketamine and found that patients started reporting improvement of depressive symptoms within a matter of a few hours [8, 9]. Thus, Ketamine has received increasing attention as a rapid-acting antidepressant, with studies suggesting that a single low-dose infusion has a beneficial although transitory effect for patients with depression, including treatment-resistant unipolar and bipolar depression [10, 11]. The antidepressant mechanisms of ketamine are controversial and seem to be various; in part via the NMDA antagonist, reduced inhibitory interneuron GABAergic transmission, a glutamate surge, an AMPA-mediated increase in BDNF release and mTORdependent neuroplasticity [12-14]. A clinical study explores, that rapamycin, a mTORC1 inhibitor would be statistically significant in prolonged rather than blocking the effect of ketamine, and people didn't relapse at 2 weeks. However, the study participants experienced significant increases in dissociative and other psychotomimetic symptoms during their infusions, as assessed by the Clinician-Administered Dissociative States Scale (CADSS) and Positive and Negative Syndrome Scale (PANSS) scores (all, P < .0001)[15, 16]. 3

3. Enantiomers of ketamine and antidepressant effects Clinically available ketamine used in many countries exists as a racemic mixture containing equal amounts of two enantiomers, S(+)- and R(–)-ketamine. S(+)-ketamine has greater potency for blocking NMDA and higher clearance for anesthesia and analgesia than R(–)-ketamine [17]. However, several animal studies have shown that R(–)-ketamine produces more potent, safer, and longer-lasting antidepressant actions. How can R(–)-ketamine induce more beneficial antidepressant effects than S(+)-ketamine? The mechanism remains elusive, but one possible explanation might be as follows. R(–)-ketamine significantly attenuates the reduction in dendritic spine density, BDNF/TrkB signaling, and synaptogenesis in the PFC, hippocampal cornu ammonis-3 (CA3) region and dentate gyrus [18-21]. In addition, a positron emission tomography study suggests that the psychotomimetic and prefrontal metabolic actions of ketamine are probably induced by S(+)-ketamine as psychotomimetic doses increase the cerebral metabolic rates of glucose (CMRglu) in the frontal cortex and thalamus; equimolar doses of R(–)-ketamine decreased CMRglu with no psychotic symptoms [22, 23]. 4. Neuromodulatory involvement of the endocannabinoid system Over the past 25 years, AEA and congeners have performed important physiological roles in the CNS and periphery. The ECB pathway shows a major part in several physiological processes involving synaptic plasticity, neuroprotection, memory and reward delivery. The ECS comprises of cannabinoid receptors, two representatives of the G-protein-coupled receptor family (e.g., CB1R, CB2R), endogenous ligands bound to these cannabinoid receptors[ e.g., anandamide and2-arachidonoylglycerol (2-AG)] and biosynthesis and degradation enzymes[ e.g., FAAH and

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MAGL] [24, 25]. This an AEA's multifaceted potential to affect nearly any human body structure (and far beyond humans across the phylogenetic tree) relies on a vast array of receptor targets that may include, alongside CB1 and CB2, TRPV1 channels, GPR55 and GPR119 and PPARs. CB1R is apparent in CNS. CB2R was deemed a "peripheral" cannabinoid receptor, unlike CB1R. Recently, though, this idea was questioned by discovering functioning CB2Rs across the CNS. Similar to CB1R, brain CB2R has many unique properties: (1) CB2Rs have low levels of expression whereas CB1Rs in the CNS, indicating that CB2Rs might not even mediate cannabis activity in normal physiological circumstances; (2) CB2Rs are complex and inducible; therefore within certain pathological situations (e.g. withdrawal, depression, fear, autism, etc.), CB2R expression might be up-regulated [26-28].

The endocannabinoid system has received

significant interest in past few decades as a possible therapeutic goal in various physiological disorders such as energy balance, appetite enhancement, blood pressure, pain management, embryogenesis, nausea and vomiting function, memory, learning and immune reaction, along with neurological conditions include Alzheimer's, Huntington's, Parkinson's and multiple sclerosis [29]. Many studies have stated that directly or indirectly stimulation of the CB1 receptor will have an antidepressant effect, although defects in this signaling might be depressogenic. A higher frequency of CB1 receptors is found throughout the brain areas involved directly with attitude regulation, i.e. hippocampus, amygdala and prefrontal cortex. In addition, research by Aso and coworkers (2011) reported that deficient mice CB1 receptors show significant improvements in the brain function of certain genetic variants with depression production. According to the findings of this study [30, 31], reports indicate that when systemically administered, CB1 receptor agonist and antagonist showed antidepressant-like symptoms. There is certain research, furthermore, that CB1 receptor ligands administration did

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not respond dramatically to depression. Ironically, both GP1a (CB2 receptor agonist) and AM630 (CB2 receptor antagonist) delivered antidepressant-like results on FST and TST. Research showed that acute or chronic therapy of CB2 receptor medications leads to antidepressant-like outcomes by regulation of CB2 expression of genes, BDNF gene, and epigenetic regulation. The research paper "Cannabinoid CB1 receptor neutral antagonist AM4113 blocks self-administration of heroin without adverse side effects in rats" tests the usefulness of CB1R neutral antagonist AM4113 in the therapy of opioid abuse of drugs and demonstrates reduction of unwanted side effects such as stress, anxiety and suicidal tendencies with SR141716 Continue to offer relevant information for endocannabinoid system activity and CB2R interaction [32-35]. 5. Relationship between the endocannabinoid system and glutaminergic transmission Glutamate is definitely the brain's most essential exciting neurotransmitter acting on 3 main cell compartments: presynaptic neurons, postsynaptic neurons, and glia. Its system works in glutamate intake, discharge, and inactivation by 2 main glutamate receptor subtypes in CNS: ionotropic and metabotropic [36-39]. iGluRs are ligand-gated ion channels that generate thrilling glutamate-evoked currents, whereas mGluRs are GPCRs that regulate biological processes by Gprotein cascades. Particular iGluR agonists confirmed the presence of AMPA (AMPARs; GluA subunits), kainate (KARs; GluK subunits) and (NMDA[ NMDARs]) receptors as 3 primary subfamilies. The 8 mGluRs, mGluR1–mGluR8, are family C GPCRs as constitutive dimers. They vary functionally from many other GPCRs by having a bigger extracellular LBD related to the7-helix TMD through a cysteine-rich domain (CRD). MGluRs are classified into subfamilies I, II or III, category I involve mGluRs 1 and 5, group II includes mGluRs 2 and 3, group III involves mGluRs 4, 6, 7 and 8 [40, 41]. The NMDA channel contains subunits NR1, NR2

6

(NR2A–NR2D),

and

NR3(NR3A

and

NR3B).

NMDA

receptor

blockers

exhibited

antidepressant-like activity in several experimental depression models, involving inescapable stressors, forced swim training, tail tension research, experienced distress models of helplessness, and recurrent moderate stress procedures. Important cognitive abilities like learning, memory formation, consolidation, mood and behavioral reactions to inducible stimuli rely heavily on NMDARs activity (Figure 1) [42, 43]. The AMPA receptor is stimulated by the presence of glutamate and typically produces a fastexcitatory synaptic signal. Its activation allows for the inward flow of sodium, causing depolarization of the neuronal membrane. The change in the intracellular charge frees the magnesium cation from the NMDA receptor, allowing the influx of calcium[44]. This channel is composed of four functionally diverse AMPA receptor subunits (GluR1–GluR4), and mature synapses are co-expressed with NMDA receptors[45, 46]. The presence of these receptors at synapses is carefully regulated to ensure proper neuronal communication[47]. Consequently, the trafficking of AMPA receptors into and out of synapses is a dynamic process and considered a significant mechanism underlying activity-induced changes in synaptic transmission[48-50] and plasticity, which are particularly instrumental in learning and memory[51, 52]. In animal models, AMPA receptor subunit 1 (GluR-A)-knockout mice (GluR-A−/−) displayed increased learned helplessness, decreased serotonin and noradrenaline (norepinephrine) levels, and disturbed glutamate homeostasis with increased glutamate levels and increased NMDA receptor expression. Moreover, a reviewed preclinical model with antidepressant-like behavioral effects and found that AMPA potentiators produced neuronal effects (e.g. brain-derived neurotrophic factor [BDNF] induction) similar to those produced by currently available antidepressants. This is in line with research suggesting that antidepressants exert their effects via a cascade of

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AMPA-mediated and NMDA-mediated events ultimately promoting synaptic plasticity[53]. In addition, compounds that augment AMPA receptor signaling or decrease NMDA receptor function may have antidepressant effects[54]. Interestingly, animal models using an AMPA antagonist (NBQX) prior to infusion found that it selectively attenuated ketamine’s antidepressant-like effects[55]. These results suggest that the antidepressant effects of ketamine are in part mediated by AMPA activation and that enhanced AMPA receptor throughput may likely account for the uniquely rapid onset of action of ketamine[56]. In general, the group I mGluRs couple to Gq /G11 and activate phospholipase Cβ, resulting in the hydrolysis of phosphoinositides and generation of inositol 1,4,5-trisphosphate (IP3 ) and diacylglycerol (Table 1). This classical pathway leads to calcium mobilization and activation of protein kinase C (PKC). However, it is now recognized that these receptors can modulate additional signaling pathways including other cascades downstream of Gq as well as pathways stemming from Gi/o, Gs, and other molecules independent of G proteins[57]. Depending on the cell type or neuronal population, group I mGluRs can activate a range of downstream effectors, including phospholipase D, protein kinase pathways such as casein kinase 1, cyclin-dependent protein kinase 5, Jun kinase, components of the mitogen-activated protein kinase/extracellular receptor kinase (MAPK/ERK) pathway, and the mammalian target of rapamycin (mTOR)/p70 S6 kinase pathway[58-61] The latter pathways, MAPK/ERK and mTOR/p70 S6 kinase, are thought to be particularly important for the regulation of synaptic plasticity by group I mGluRs. In contrast to the group I mGluRs, group II and III mGluRs are coupled predominantly to Gi/o proteins. Gi/o linked receptors are classically coupled to the inhibition of adenylyl cyclase and directly regulate ion channels and other downstream signaling partners via the liberation of Gβγ subunits. As with group I mGluRs, it is becoming increasingly appreciated that group II and

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group III mGluRs also couple to other signaling pathways, including activation of MAPK and phosphatidylinositol 3-kinase PI3 kinase pathways[62] providing further complexity regarding the mechanisms by which these receptors can regulate synaptic transmission. In this biological context, endocannabinoids are released to retain NMDA receptor activity within physiological limits. After a rise in intracellular calcium or activation of certain neurotransmitter receptors, endocannabinoids are synthesized by cleavage of phospholipid precursors that are present in cellular membranes[63-65]. Endocannabinoids themselves function as neuromodulators that are released by post-synaptic neurons and bind to the presynaptic CB1Rs to modulate the release of neurotransmitters, such as gamma-aminobutyric-acid (GABA), glutamate, and dopamine (DA)[66-68]. 6. Biomolecular and mechanistic exploration of ketamine in depression A recent study exhibit that ketamine at low doses enhances the level of endocannabinoids in the central nervous system and produces biological response by activation of the CB1 receptor [69].One more study data suggest that ketamine, in the presence of a nociceptive stimulus, induces a selective release of AEA levels and subsequent CB1 cannabinoid activation at the peripheral level[70]. At present, there is considerable evidence involving the endocannabinoid system in eliciting potent effects on neurotransmission, neuroendocrine, and inflammatory processes, which are all known to be deranged in depression. Several synthetic cannabinomimetic drugs are being developed to treat pain and depression. In addition, most often it increases histone acetylation referred by the CB1 agonist ∆(9)-tetrahydrocannabinol (THC) [71-74]. ketamine stimulates the phosphorylation (Ser259/Ser498) and nuclear export of histone deacetylase 5 (HDAC5)[75]. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine. In the

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preclinical study exhibit that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine[76]. Moreover, Recent studies in the neocortex have shown that endocannabinoid synthesis and release can be rapidly mobilized by BDNF−trkB signaling. In the neocortical layer 2/3, the acute application of BDNF rapidly suppresses GABAergic transmission via the release of endocannabinoids from the postsynaptic pyramidal cell, which acts in a retrograde manner to suppress presynaptic transmitter release[77]. This effect of BDNF is initiated by postsynaptic trkB signaling, requires downstream PLC signaling, and is independent of mGluR activation[7881]. The trkB receptor is the major receptor for BDNF signaling in the brain and mediates most of the effects of BDNF on synaptic transmission and plasticity. Upon binding to trkB receptors, BDNF stimulates at least three major downstream intracellular signaling pathways via tyrosine phosphorylation,

namely,

Ras/mitogen-activated

protein

kinase

(MAPK)

pathway,

phosphatidylinositol 3-kinases (PI3K)/Akt pathway, and phospholipase Cγ (PLCγ) pathway. Activation of PLCγ leads to cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces Ca2+ release from intracellular Ca2+ stores upon binding to its receptor and thus increases intracellular Ca2+ concentration (Figure 2) [82, 83]. 7. Association of endocannabinoid and ketamine mediated psychoactivity

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There are several critical problems associated with ketamine to overcome. First, ketamine is a drug of abuse and has serious side effects, so new agents with a reduced side effect profile are needed. Second, although ketamine produces a rapid antidepressant response, the effects last for about 1 week, at which time patients typically relapse. New agents that can be used on a daily, sustained basis are needed. Third, studies are needed to understand why new ketamine-induced synapses are lost after 1 week and whether there are approaches or agents (or both) that can sustain the synaptic as well as the therapeutic actions of ketamine. Fourth, additional research is needed to fully understand the cellular mechanisms underlying the actions of ketamine and other rapid-acting agents [84, 85] [86]. Several lines of evidence suggest that the glutamatergic NMDA receptor is involved in schizophrenia pathophysiology. Post-mortem studies have revealed a lower density of glutamatergic receptors in patients with schizophrenia. Other studies of cerebrospinal fluid reported lower levels of glutamate in patients with schizophrenia in healthy comparison subjects. The most compelling evidence is provided by the psychomimetic effects of the NMDA antagonists phencyclidine and ketamine. Recently, much interest has been given to the study related to the role of the NMDA receptor in the pathophysiology of schizophrenia by the administration of sub-anesthetic doses of ketamine. A phencyclidine hydrochloride derivate, ketamine, is a dissociative anesthetic and a non-competitive antagonist of the NMDA receptor. In healthy subjects, ketamine produces 1) positive symptoms of psychosis, such as illusions, thought disorder and delusions; 2) negative symptoms similar to those associated with schizophrenia including blunted emotional responses, emotional detachment, and psychomotor retardation; 3) cognitive impairments, in particular impairments on tests of frontal cortical function including increased distractibility, reduced verbal fluency and poorer performance on

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the Wisconsin Card Sorting Test. During smooth pursuit eye tracking, ketamine induces nystagmus as well as abnormalities which are among the characteristics of schizophrenia. In patients with schizophrenia, the administration of ketamine produces activation of their psychotic symptoms, which have striking similarities to symptoms of their usual psychotic episodes. Ketamine effects on memory and other cognitive functions in schizophrenic patients are controversial. The psychomimetic effects of ketamine are transitional, reversible and influenced by time, dose and administration conditions. Susceptibility to the psychotomimetic effects of ketamine is minimal or absent in children and becomes maximal in early adulthood. The similarity between ketamine effects and endogenous psychoses created interest in the capacity of antipsychotic medications to block ketamine effects. Haloperidol failed to block this ketamineinduced psychomimetic effects in healthy subjects and in schizophrenic patients. However, clozapine, the prototype of atypical antipsychotic agents significantly reduced the ketamineinduced increase in positive symptoms in schizophrenic patients. Recently, data from clinical studies exhibit lamotrigine significantly decreased ketamine-induced positive and negative symptoms in healthy subjects [87]. Glutamate is the primary excitatory neurotransmitter in the mammalian brain. Disturbances in glutamate-mediated neurotransmission have been increasingly documented in a range of neuropsychiatric disorders including schizophrenia, substance abuse, mood disorders, Alzheimer's disease, and autism spectrum disorders [33, 88]. Glutamatergic theories of schizophrenia are based on the ability of NMDA receptor antagonists to induce schizophrenialike symptoms, as well as emergent literature documenting disturbances of NMDA receptorrelated gene expression and metabolic pathways in schizophrenia. Research over the past two decades has highlighted promising new targets for drug development based on potential pre- and

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postsynaptic, and glial mechanisms leading to NMDA receptor dysfunction. Reduced NMDA receptor activity on inhibitory neurons leads to the disinhibition of glutamate neurons increasing the synaptic activity of glutamate, especially in the prefrontal cortex [89]. Studies in humans have indicated that abuse of smoked cannabis can promote psychosis and even circumstantially precipitate symptoms of schizophrenia, although the latter appears to require a prior vulnerability in the individual. It is possible that cannabinoids provoke psychosis/schizophrenia reflecting a mechanism common to neuroprotection: the reduction of NMDA receptor activity. Cannabinoids are proposed to produce such effect by reducing the pre-synaptic release of glutamate or interfering with post-synaptic NMDA receptor-regulated signaling pathways [90, 91]. Multiple studies have implicated ECB system dysregulation in the pathophysiology of schizophrenia, including alterations in CB1R expression. Post-mortem schizophrenia studies report alterations in the ionotropic glutamatergic NMDA receptor and its obligatory GluN1 subunit [92] and GABAA Receptor [93] as well as a reduction in glutamate decarboxylase 67 (GAD67; the ratelimiting enzyme that converts glutamate to GABA) and the calcium-binding protein parvalbumin (PV), expressed on GABAergic interneurons [94]. Moreover, the dopaminergic signaling dysregulation such as that observed in schizophrenic patients. the increased activity of GPCRs such as dopamine 2 receptors (D2Rs) was initially proposed to decrease NMDA receptor activity in schizophrenia[95-97]. In addition to a study exhibit, acute exposure to CB1R agonists (e.g., THC; CP 55,940; WIN 55,212-2; HU 210) augments brain DA transmission[98]. Glutamatergic theories of schizophrenia have been based on the ability of NMDA receptor antagonists, such as phencyclidine (PCP) and ketamine, to induce schizophrenia-like symptoms and on disturbances of NMDA receptor-related gene expression and metabolic pathways accounting mainly for negative symptoms and some

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cognitive dysfunctions of the disorder. Reduced NMDA receptor activity on inhibitory (GABAergic) neurons leads to disinhibition of glutamate neurons. Theoretically, such abnormally increased glutamatergic activity through AMPA and metabotropic glutamate (mGLUT) receptors causes overactivation of the mesolimbic and underactivation of the mesocortical dopaminergic pathways, leading to morphological and structural brain changes resulting in psychosis [95, 99-101]. In addition, endocannabinoids are released on demand by the postsynaptic neurons and travel retrogradely across the synapse, binding to and activating CB1Rs located on the presynaptic terminals [102]. Such activation results in the short- or long-term decrease in neurotransmitter release[103]. The effects of cannabinoids/endocannabinoids on dopamine transmission and dopamine-related behaviors are generally indirect and exerted through decreased neurotransmission[104]. Thus, cannabinoid agonists reduce glutamate release from hippocampal neurons, which results in a net increase in cortical pyramidal neuron excitability via the activation of CB1Rs located on inhibitory GABAergic cells [105, 106]. All these mechanisms likely contribute to cannabinoid-induced learning and memory impairments. Furthermore, certain endocannabinoids (e.g., N-arachidonoyl dopamine and AEA) may directly activate transient receptor potential vanilloid 1 channel (TRPV1) receptors[102, 107]. thereby allowing direct facilitatory regulation of dopamine function (e.g., at the nucleus accumbens) that influences the motivated behavior and reward process [108]. Conclusion An important exploration that exhibits the research summarized in this review included the components of the ECS can be pharmacologically upregulated by ketamine to achieve favorable outcomes regarding the antidepressant effect of ketamine by blocking the effect of glutamate and concentration within the physiological limit. Moreover, there is an overwhelming burden of 14

evidence that the ECS and all its components are an attractive target for psychoactive phenomena of ketamine. Future work must focus on detailing the mechanisms by which altered ECB signaling in the brain yields protective and detrimental effects in the CNS, particularly as it relates to the chronic use of a low dose of ketamine. Answering these questions could provide improved therapeutics for antidepressants and their associated conditions. References [1] E.E. Acevedo-Diaz, G.W. Cavanaugh, D. Greenstein, C. Kraus, B. Kadriu, C.A. Zarate, L.T. Park, Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression, Journal of affective disorders, (2019). [2] F. Agboola, S.J. Atlas, D.R. Touchette, K. Fazioli, S.D. Pearson, The Effectiveness and Value of Esketamine for the Management of Treatment-Resistant Depression, Journal of managed care & specialty pharmacy, 26 (2020) 16-20. [3] A. Baker, N. Simon, A. Keshaviah, A. Farabaugh, T. Deckersbach, J.J. Worthington, E. Hoge, M. Fava, M.P. Pollack, Anxiety Symptoms Questionnaire (ASQ): development and validation, General psychiatry, 32 (2019) e100144. [4] G. Gupta, R. Wadhwa, P. Pandey, S.K. Singh, M. Gulati, S. Sajita, M. Mehta, A.K. Singh, H. Dureja, T. Collet, Obesity and Diabetes: Pathophysiology of Obesity-Induced Hyperglycemia and Insulin Resistance, Pathophysiology of Obesity-Induced Health Complications, Springer2020, pp. 81-97. [5] A. Madhu, G. Gupta, B. Arali, D. K Chellappan, K. Dua, Anti-psychotic activity of aqueous root extract of Hemidesmus indicus: a time bound study in rats, Recent patents on drug delivery & formulation, 11 (2017) 36-41.

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[6] R.J. Baldessarini, G.H. Vazquez, L. Tondo, Bipolar depression: a major unsolved challenge, International journal of bipolar disorders, 8 (2020) 1. [7] S. Bhardwaj, K. Garg, S. Devgan, Comparison of opioid-based and opioid-free TIVA for laparoscopic urological procedures in obese patients, Journal of anaesthesiology, clinical pharmacology, 35 (2019) 481-486. [8] K.M. Bozymski, E.L. Crouse, E.N. Titus-Lay, C.A. Ott, J.L. Nofziger, C.K. Kirkwood, Esketamine: A Novel Option for Treatment-Resistant Depression, The Annals of pharmacotherapy, (2019) 1060028019892644. [9] A. Bransi, L. Winter, A. Glahn, K.G. Kahl, [Addictive disorders in physicians], Der Nervenarzt, 91 (2020) 77-90. [10] C.A. Browne, M.L. Jacobson, I. Lucki, Novel Targets to Treat Depression: Opioid-Based Therapeutics, Harvard review of psychiatry, 28 (2020) 40-59. [11] M. Cai, H. Wang, X. Zhang, Potential Anti-Depressive Treatment Maneuvers from Bench to Bedside, Advances in experimental medicine and biology, 1180 (2019) 277-295. [12] Q. Chen, J. Dong, J. Luo, L. Ren, S. Min, X. Hao, Q. Luo, J. Chen, X. Li, Effects of LowDose Ketamine on the Antidepressant Efficacy and Suicidal Ideations in Patients Undergoing Electroconvulsive Therapy, The journal of ECT, (2020). [13] G. Gupta, R. Singh, S.R. David, R.K. Verma, Effect of rosiglitazone, a PPAR‐γ ligand on haloperidol‐induced catalepsy, CNS neuroscience & therapeutics, 19 (2013) 724. [14] V.K. Rapalli, G. Singhvi, S.K. Dubey, G. Gupta, D.K. Chellappan, K. Dua, Emerging landscape in psoriasis management: From topical application to targeting biomolecules, Biomedicine & Pharmacotherapy, 106 (2018) 707-713.

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[15] C. Abdallah, L. Averill, R. Gueorguieva, S. Goktas, P. Purohit, M. Ranganathan, D. D’Souza, R. Formica, S. Southwick, R. Duman, G. Sanacora, J. Krystal, Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the Antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial, 2018. [16] G. Gupta, G. Singhvi, D.K. Chellappan, S. Sharma, A. Mishra, R. Dahiya, K. Dua, Peroxisome proliferator-activated receptor gamma: promising target in glioblastoma, Panminerva medica, 60 (2018) 109-116. [17] J. Muller, S. Pentyala, J. Dilger, S. Pentyala, Ketamine enantiomers in the rapid and sustained antidepressant effects, Therapeutic Advances in Psychopharmacology, 6 (2016) 185192. [18] A. Christensen, J. Pruskowski, The Role of Ketamine in Depression #384, Journal of palliative medicine, 23 (2020) 136-138. [19] G. Gupta, I. Kazmi, M. Afzal, M. Rahman, S. Saleem, M.S. Ashraf, M.J. Khusroo, K. Nazeer, S. Ahmed, M. Mujeeb, Sedative, antiepileptic and antipsychotic effects of Viscum album L.(Loranthaceae) in mice and rats, Journal of ethnopharmacology, 141 (2012) 810-816. [20] M. Mehta, D. Tewari, G. Gupta, R. Awasthi, H. Singh, P. Pandey, D.K. Chellappan, R. Wadhwa, T. Collet, P.M. Hansbro, Oligonucleotide therapy: An emerging focus area for drug delivery in chronic inflammatory respiratory diseases, Chemico-biological interactions, (2019). [21] S. Rawat, S. Pathak, G. Gupta, S.K. Singh, H. Singh, A. Mishra, R. Gilhotra, Recent updates on daidzein against oxidative stress and cancer, EXCLI journal, 18 (2019) 950. [22] R. Corne, R. Mongeau, [Neurotrophic mechanisms of psychedelic therapy], Biologie aujourd'hui, 213 (2019) 121-129.

17

[23] F.S. Correia-Melo, G.C. Leal, F. Vieira, A.P. Jesus-Nunes, R.P. Mello, G. Magnavita, A.T. Caliman-Fontes, M.V.F. Echegaray, I.D. Bandeira, S.S. Silva, D.E. Cavalcanti, L. Araujo-deFreitas, L.M. Sarin, M.A. Tuena, C. Nakahira, A.S. Sampaio, J.A. Del-Porto, G. Turecki, C. Loo, A.L.T. Lacerda, L.C. Quarantini, Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, noninferiority study, Journal of affective disorders, (2019). [24] R.M. Dale, K.A. Bryant, N.R. Thompson, Metabolic Syndrome Rather Than Body Mass Index Is Associated With Treatment Response to Ketamine Infusions, Journal of clinical psychopharmacology, 40 (2020) 75-79. [25] S. Deyama, R.S. Duman, Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine, Pharmacology, biochemistry, and behavior, 188 (2020) 172837. [26] R.S. Duman, S. Deyama, M.V. Fogaca, Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants, The European journal of neuroscience, (2019). [27] G. Gupta, R. Dahiya, M. Singh, J. Tiwari, S. Sah, M. Ashwathanarayana, G. Krishna, K. Dua, Role of liraglutide in a major complication of diabetes: A critical review of clinical studies, Bull Pharm Res, 8 (2018) 155-164. [28] X. Liu, R.K. Sharma, A. Mishra, G.K. Chinnaboina, G. Gupta, M. Singh, Role of Aqueous Extract of the Wood Ear Mushroom, Auricularia polytricha (Agaricomycetes), in Avoidance of Haloperidol-lnduced Catalepsy via Oxidative Stress in Rats, International journal of medicinal mushrooms, 21 (2019).

18

[29] S. Eberl, L. Koers, J. van Hooft, E. de Jong, J. Hermanides, M.W. Hollmann, B. Preckel, The effectiveness of a low-dose esketamine versus an alfentanil adjunct to propofol sedation during endoscopic retrograde cholangiopancreatography: A randomised controlled multicentre trial, European journal of anaesthesiology, (2019). [30] E. Falk, D. Schlieper, P. van Caster, M.J. Lutterbeck, J. Schwartz, J. Cordes, I. Grau, P. Kienbaum, M. Neukirchen, A rapid positive influence of S-ketamine on the anxiety of patients in palliative care: a retrospective pilot study, BMC palliative care, 19 (2020) 1. [31] I.P. Fallon, M.K. Tanner, B.N. Greenwood, M.V. Baratta, Sex differences in resilience: Experiential factors and their mechanisms, The European journal of neuroscience, (2019). [32] M.E. Frizzo, The Effect of Glutamatergic Modulators on Extracellular Glutamate: How Does this Information Contribute to the Discovery of Novel Antidepressants?, Current therapeutic research, clinical and experimental, 91 (2019) 25-32. [33] G. Gupta, M. Bebawy, T.d.J.A. Pinto, D.K. Chellappan, A. Mishra, K. Dua, Role of the tristetraprolin (zinc finger protein 36 homolog) gene in cancer, Critical Reviews™ in Eukaryotic Gene Expression, 28 (2018). [34] G. Gupta, D.K. Chellappan, M. Agarwal, M. Ashwathanarayana, S. Nammi, K. Pabreja, K. Dua, Pharmacological evaluation of the recuperative effect of morusin against aluminium trichloride (AlCl3)-induced memory impairment in rats, Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Central Nervous System Agents), 17 (2017) 196-200. [35] P. Sharma, M. Mehta, D.S. Dhanjal, S. Kaur, G. Gupta, H. Singh, L. Thangavelu, S.R. Kumar, M. Tambuwala, H.A. Bakshi, Emerging trends in the novel drug delivery approaches for the treatment of lung cancer, Chemico-biological interactions, (2019).

19

[36] C. Gastaldon, D. Papola, G. Ostuzzi, C. Barbui, Esketamine for treatment resistant depression: a trick of smoke and mirrors?, Epidemiology and psychiatric sciences, 29 (2019) e79. [37] S. Sharma, S. Pathak, G. Gupta, S.K. Sharma, L. Singh, R.K. Sharma, A. Mishra, K. Dua, Pharmacological evaluation of aqueous extract of syzigium cumini for its antihyperglycemic and antidyslipidemic properties in diabetic rats fed a high cholesterol diet—Role of PPARγ and PPARα, Biomedicine & Pharmacotherapy, 89 (2017) 447-453. [38] K.P. Sunkara, G. Gupta, P.M. Hansbro, K. Dua, M. Bebawy, Functional relevance of SATB1 in immune regulation and tumorigenesis, Biomedicine & Pharmacotherapy, 104 (2018) 87-93. [39] R. Wadhwa, P. Pandey, G. Gupta, T. Aggarwal, N. Kumar, M. Mehta, S. Satija, M. Gulati, J. Madan, H. Dureja, Emerging Complexity and the Need for Advanced Drug Delivery in Targeting Candida Species, Current topics in medicinal chemistry, 19 (2019) 2593-2609. [40] J.R. Gilbert, E.D. Ballard, C.S. Galiano, A.C. Nugent, C.A. Zarate, Jr., Magnetoencephalographic Correlates of Suicidal Ideation in Major Depression, Biological psychiatry. Cognitive neuroscience and neuroimaging, (2019). [41] B.D. Hare, S. Pothula, R.J. DiLeone, R.S. Duman, Ketamine increases vmPFC activity: Effects of (R)- and (S)-stereoisomers and (2R,6R)-hydroxynorketamine metabolite, Neuropharmacology, 166 (2020) 107947. [42] M.F. Ho, C. Zhang, L. Zhang, H. Li, R.M. Weinshilboum, Ketamine and Active Ketamine Metabolites Regulate STAT3 and the Type I Interferon Pathway in Human Microglia: Molecular Mechanisms Linked to the Antidepressant Effects of Ketamine, Frontiers in pharmacology, 10 (2019) 1302.

20

[43] M.E. Klein, J. Chandra, S. Sheriff, R. Malinow, Opioid system is necessary but not sufficient for antidepressive actions of ketamine in rodents, Proceedings of the National Academy of Sciences of the United States of America, (2020). [44] R. Machado-Vieira, G. Salvadore, L.A. Ibrahim, N. Diaz-Granados, C.A. Zarate, Jr., Targeting glutamatergic signaling for the development of novel therapeutics for mood disorders, Current pharmaceutical design, 15 (2009) 1595-1611. [45] G. Sanacora, C.A. Zarate, J.H. Krystal, H.K. Manji, Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders, Nature reviews. Drug discovery, 7 (2008) 426-437. [46] J.J. Zhu, Y. Qin, M. Zhao, L. Van Aelst, R. Malinow, Ras and Rap control AMPA receptor trafficking during synaptic plasticity, Cell, 110 (2002) 443-455. [47] J.A. Esteban, AMPA receptor trafficking: a road map for synaptic plasticity, Molecular interventions, 3 (2003) 375-385. [48] V. Anggono, R.L. Huganir, Regulation of AMPA receptor trafficking and synaptic plasticity, Current opinion in neurobiology, 22 (2012) 461-469. [49] G. Gupta, D.K. Chellappan, P. Hansbro, M. Bebawy, K. Dua, Tumor suppressor role of miR-503, Panminerva medica, 60 (2018) 17-24. [50] G. Gupta, D.K. Chellappan, I.S. Kikuchi, T.d.J.A. Pinto, K. Pabreja, M. Agrawal, Y. Singh, J. Tiwari, K. Dua, Nephrotoxicity in rats exposed to paracetamol: the protective role of moralbosteroid, a steroidal glycoside, Journal of Environmental Pathology, Toxicology and Oncology, 36 (2017). [51] R.C. Malenka, R.A. Nicoll, Long-term potentiation--a decade of progress?, Science (New York, N.Y.), 285 (1999) 1870-1874.

21

[52] R. Malinow, R.C. Malenka, AMPA receptor trafficking and synaptic plasticity, Annual review of neuroscience, 25 (2002) 103-126. [53] D. Bleakman, A. Alt, J.M. Witkin, AMPA receptors in the therapeutic management of depression, CNS & neurological disorders drug targets, 6 (2007) 117-126. [54] S. Chourbaji, M.A. Vogt, F. Fumagalli, R. Sohr, A. Frasca, C. Brandwein, H. Hortnagl, M.A. Riva, R. Sprengel, P. Gass, AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression, FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 22 (2008) 3129-3134. [55] S. Maeng, C.A. Zarate, Jr., J. Du, R.J. Schloesser, J. McCammon, G. Chen, H.K. Manji, Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3hydroxy-5-methylisoxazole-4-propionic acid receptors, Biological psychiatry, 63 (2008) 349352. [56] C. Zarate, Jr., R. Machado-Vieira, I. Henter, L. Ibrahim, N. Diazgranados, G. Salvadore, Glutamatergic modulators: the future of treating mood disorders?, Harvard review of psychiatry, 18 (2010) 293-303. [57] E. Hermans, R.A. Challiss, Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors, The Biochemical journal, 359 (2001) 465-484. [58] S. Neyman, D. Manahan-Vaughan, Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro, The European journal of neuroscience, 27 (2008) 1345-1352.

22

[59] L. Hou, E. Klann, Activation of the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent longterm depression, J Neurosci, 24 (2004) 6352-6361. [60] G. Page, F.A. Khidir, S. Pain, L. Barrier, B. Fauconneau, O. Guillard, A. Piriou, J. Hugon, Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes, Neurochemistry international, 49 (2006) 413421. [61] X.M. Li, C.C. Li, S.S. Yu, J.T. Chen, K. Sabapathy, D.Y. Ruan, JNK1 contributes to metabotropic glutamate receptor-dependent long-term depression and short-term synaptic plasticity in the mice area hippocampal CA1, The European journal of neuroscience, 25 (2007) 391-396. [62] L. Iacovelli, V. Bruno, L. Salvatore, D. Melchiorri, R. Gradini, A. Caricasole, E. Barletta, A. De Blasi, F. Nicoletti, Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways, Journal of neurochemistry, 82 (2002) 216-223. [63] T.F. Freund, I. Katona, D. Piomelli, Role of endogenous cannabinoids in synaptic signaling, Physiological reviews, 83 (2003) 1017-1066. [64] M. Altamish, V.P. Samuel, R. Dahiya, Y. Singh, P.K. Deb, H.A. Bakshi, M.M. Tambuwala, D.K. Chellappan, T. Collet, K. Dua, Molecular signaling of G‐protein‐coupled receptor in chronic heart failure and associated complications, Drug Development Research, (2019). [65] D.K. Chellappan, K.H. Leng, L.J. Jia, N.A.B.A. Aziz, W.C. Hoong, Y.C. Qian, F.Y. Ling, G.S. Wei, T. Ying, J. Chellian, The role of bevacizumab on tumour angiogenesis and in the

23

management of gynaecological cancers: A review, Biomedicine & Pharmacotherapy, 102 (2018) 1127-1144. [66] V. Di Marzo, M. Bifulco, L. De Petrocellis, The endocannabinoid system and its therapeutic exploitation, Nature reviews. Drug discovery, 3 (2004) 771-784. [67] G.E. Terry, J.S. Liow, S.S. Zoghbi, J. Hirvonen, A.G. Farris, A. Lerner, J.T. Tauscher, J.M. Schaus, L. Phebus, C.C. Felder, C.L. Morse, J.S. Hong, V.W. Pike, C. Halldin, R.B. Innis, Quantitation of cannabinoid CB1 receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand, NeuroImage, 48 (2009) 362-370. [68] S.D. McAllister, M. Glass, CB₁ and CB₂ receptor-mediated signalling: a focus on endocannabinoids, Prostaglandins, Leukotrienes and Essential Fatty Acids, 66 (2002) 161-171. [69] D.D.F. Pacheco, T.R.L. Romero, I.D.G. Duarte, Ketamine induces central antinociception mediated by endogenous cannabinoids and activation of CB1 receptors, Neuroscience letters, 699 (2019) 140-144. [70] R.C.M. Ferreira, M.G.M. Castor, F. Piscitelli, V. Di Marzo, I.D.G. Duarte, T.R.L. Romero, The Involvement of the Endocannabinoid System in the Peripheral Antinociceptive Action of Ketamine, The journal of pain : official journal of the American Pain Society, 19 (2018) 487495. [71] T. Hayase, Putative Epigenetic Involvement of the Endocannabinoid System in Anxietyand Depression-Related Behaviors Caused by Nicotine as a Stressor, PLoS One, 11 (2016) e0158950-e0158950. [72] Y. Chan, S.W. Ng, J.Z.X. Tan, G. Gupta, M.M. Tambuwala, H.A. Bakshi, H. Dureja, K. Dua, M. Ishaq, V. Caruso, Emerging therapeutic potential of the iridoid molecule, asperuloside:

24

A snapshot of its underlying molecular mechanisms, Chemico-Biological Interactions, (2019) 108911. [73] D.K. Chellappan, N.J. Yee, B.J. Kaur Ambar Jeet Singh, J. Panneerselvam, T. Madheswaran, J. Chellian, S. Satija, M. Mehta, M. Gulati, G. Gupta, Formulation and characterization of glibenclamide and quercetin-loaded chitosan nanogels targeting skin permeation, Therapeutic delivery, 10 (2019) 281-293. [74] P. Das, G. Gupta, V. Velu, R. Awasthi, K. Dua, H. Malipeddi, Formation of struvite urinary stones and approaches towards the inhibition—A review, Biomedicine & Pharmacotherapy, 96 (2017) 361-370. [75] M. Choi, S.H. Lee, S.E. Wang, S.Y. Ko, M. Song, J.-S. Choi, Y.-S. Kim, R.S. Duman, H. Son, Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats, Proceedings of the National Academy of Sciences, 112 (2015) 15755-15760. [76] M. Choi, S.H. Lee, M.H. Park, Y.S. Kim, H. Son, Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats, Biochemical and biophysical research communications, 489 (2017) 420-425. [77] F. Lemtiri-Chlieh, E.S. Levine, BDNF Evokes Release of Endogenous Cannabinoids at Layer 2/3 Inhibitory Synapses in the Neocortex, Journal of Neurophysiology, 104 (2010) 19231932. [78] L. Zhao, E.S. Levine, BDNF-endocannabinoid interactions at neocortical inhibitory synapses require phospholipase C signaling, Journal of Neurophysiology, 111 (2014) 1008-1015.

25

[79] D.K. Chellappan, Z.Y. Ng, J.-Y. Wong, A. Hsu, P. Wark, N. Hansbro, J. Taylor, J. Panneerselvam, T. Madheswaran, G. Gupta, Immunological axis of curcumin-loaded vesicular drug delivery systems, Future Science Ltd London, UK, 2018. [80] K. Dua, M. Bebawy, R. Awasthi, R.K. Tekade, M. Tekade, G. Gupta, A.P. De Jesus, P.M. Hansbro, Application of chitosan and its derivatives in nanocarrier based pulmonary drug delivery systems, Pharmaceutical nanotechnology, 5 (2017) 243-249. [81] R.K. Gautam, G. Gupta, S. Sharma, K. Hatware, K. Patil, K. Sharma, S. Goyal, D.K. Chellappan, K. Dua, Rosmarinic acid attenuates inflammation in experimentally induced arthritis in Wistar rats, using Freund’s complete adjuvant, International journal of rheumatic diseases, 22 (2019) 1247-1254. [82] A.D. Stoker, D.M. Rosenfeld, M.R. Buras, J.M. Alvord, A.W. Gorlin, Evaluation of Clinical Factors Associated with Adverse Drug Events in Patients Receiving Sub-Anesthetic Ketamine Infusions, Journal of pain research, 12 (2019) 3413-3421. [83] Y. Tan, Y. Fujita, Y. Qu, L. Chang, Y. Pu, S. Wang, X. Wang, K. Hashimoto, Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent repeated intermittent administration of (R)-ketamine, but not (S)-ketamine: Role of BDNF-TrkB signaling, Pharmacology, biochemistry, and behavior, 188 (2020) 172839. [84] S.L. Thompson, A.C. Welch, J. Iourinets, S.C. Dulawa, Ketamine induces immediate and delayed alterations of OCD-like behavior, Psychopharmacology, (2020). [85] L. Vlerick, M. Devreese, K. Peremans, R. Dockx, S. Croubels, L. Duchateau, I. Polis, Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs, PloS one, 15 (2020) e0227762.

26

[86] J.M. Witkin, mGlu2/3 receptor antagonism: A mechanism to induce rapid antidepressant effects without ketamine-associated side-effects, Pharmacology, biochemistry, and behavior, (2020) 172854. [87] G. Gupta, J. Tiwari, R. Dahiya, R. Kumar Sharma, A. Mishra, K. Dua, Recent updates on neuropharmacological effects of luteolin, EXCLI journal, 17 (2018) 211-214. [88] K. Dua, J.R. Madan, D.K. Chellappan, G. Gupta, Nanotechnology in drug delivery gaining new perspectives in respiratory diseases, Panminerva medica, 60 (2018) 135. [89] K.S. Zimmermann, R. Richardson, K.D. Baker, Esketamine as a treatment for paediatric depression: questions of safety and efficacy, The lancet. Psychiatry, (2020). [90] D.K. Chellappan, J. Chellian, Z.Y. Ng, Y.J. Sim, C.W. Theng, J. Ling, M. Wong, J.H. Foo, G.J. Yang, L.Y. Hang, The role of pazopanib on tumour angiogenesis and in the management of cancers: a review, Biomedicine & Pharmacotherapy, 96 (2017) 768-781. [91] G. Gupta, M. Afzal, S.R. David, R. Verma, M. Candaswamy, F. Anwar, Anticonvulsant activity of Morus alba and its effect on brain gamma-aminobutyric acid level in rats, Pharmacognosy research, 6 (2014) 188. [92] V.S. Catts, Y.L. Lai, C.S. Weickert, T.W. Weickert, S.V. Catts, A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?, Biological psychology, 116 (2016) 57-67. [93] G. Gonzalez-Burgos, D.A. Lewis, GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia, Schizophrenia bulletin, 34 (2008) 944-961.

27

[94] J. Mao, T. Li, D. Fan, H. Zhou, J. Feng, L. Liu, C. Zhang, X. Wang, Abnormal expression of rno_circRNA_014900 and rno_circRNA_005442 induced by ketamine in the rat hippocampus, BMC psychiatry, 20 (2020) 1. [95] B. Moghaddam, D. Javitt, From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment, Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 37 (2012) 4-15. [96] L.V. Kristiansen, I. Huerta, M. Beneyto, J.H. Meador-Woodruff, NMDA receptors and schizophrenia, Current opinion in pharmacology, 7 (2007) 48-55. [97] A. Mechri, M. Saoud, G. Khiari, T. d'Amato, J. Dalery, L. Gaha, [Glutaminergic hypothesis of schizophrenia: clinical research studies with ketamine], L'Encephale, 27 (2001) 53-59. [98] E.D. French, ∆9-Tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors, Neuroscience letters, 226 (1997) 159162. [99] J. Savitz, The kynurenine pathway: a finger in every pie, Mol Psychiatry, 25 (2020) 131147. [100] J.M. Stone, P.D. Morrison, L.S. Pilowsky, Review: Glutamate and dopamine dysregulation in schizophrenia — a synthesis and selective review, Journal of Psychopharmacology, 21 (2007) 440-452. [101] D.C. Javitt, D. Schoepp, P.W. Kalivas, N.D. Volkow, C. Zarate, K. Merchant, M.F. Bear, D. Umbricht, M. Hajos, W.Z. Potter, C.-M. Lee, Translating Glutamate: From Pathophysiology to Treatment, Science Translational Medicine, 3 (2011) 102mr102-102mr102.

28

[102] M. Melis, M. Pistis, Hub and switches: endocannabinoid signalling in midbrain dopamine neurons, Philosophical Transactions of the Royal Society B: Biological Sciences, 367 (2012) 3276-3285. [103] I. Katona, T.F. Freund, Multiple functions of endocannabinoid signaling in the brain, Annual review of neuroscience, 35 (2012) 529-558. [104] I. Ibarra-Lecue, F. Pilar-Cuéllar, C. Muguruza, E. Florensa-Zanuy, Á. Díaz, L. Urigüen, E. Castro, A. Pazos, L.F. Callado, The endocannabinoid system in mental disorders: Evidence from human brain studies, Biochemical Pharmacology, 157 (2018) 97-107. [105] J.M. Sullivan, Cellular and molecular mechanisms underlying learning and memory impairments produced by cannabinoids, Learning & memory (Cold Spring Harbor, N.Y.), 7 (2000) 132-139. [106] S.R. Laviolette, A.A. Grace, The roles of cannabinoid and dopamine receptor systems in neural emotional learning circuits: implications for schizophrenia and addiction, Cellular and molecular life sciences : CMLS, 63 (2006) 1597-1613. [107] K. Starowicz, S. Nigam, V. Di Marzo, Biochemistry and pharmacology of endovanilloids, Pharmacology & Therapeutics, 114 (2007) 13-33. [108] J. Fernández-Ruiz, M. Hernández, J.A. Ramos, Cannabinoid–Dopamine Interaction in the Pathophysiology and Treatment of CNS Disorders, CNS Neuroscience & Therapeutics, 16 (2010) e72-e91.

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Table1: iexplores ithe ineuronal ilocation iand imechanism imediated iby imetabotropic glutamate ireceptor igroup iI, iII, iIII

i

Group

Receptor

Neuronal ilocalization

Signaling itransmission imechanism Stimulation iof iPLC Stimulation iof iAC (some isystems) Phosphorylation iof iMAPK iand Inhibition iof iAC Activation iof iK+ ichannels Inhibition iof iCa++ ichannels Inhibition iof iAC Activation iof iK+ ichannels Inhibition iof iCa++ ichannels Stimulation iof icGMP Phosphodiesterase

Group iI

mGluR1 mGluR5

Postsynaptic

Group iII

mGluR2 mGluR3

Presynaptic Postsynaptic

Group iIII

mGluR4 mGluR7 mGluR8

Presynaptic

mGluR6

Postsynaptic

Figure 1: Relationship between endocannabinoid and glutaminergic system

Figure 2: Biomolecular and mechanistic exploration of ketamine in depression

Highlights: 1. Ketamine is thought to act by blocking N-methyl-d-aspartate (NMDA) receptors in the brain 2. Ketamine is an arylcycloalkylamine that is structurally related to phencyclidine (PCP) 3. This review exploring the molecular targets for the treatment and psychomimetic phenomena of the ketamine

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: