Non-competitive N-methyl-D-aspartate Receptor Research Articles

Ketamine exerts dual effects on the apoptosis of primary cultured hippocampal neurons from fetal rats in vitro.

Ketamine, a noncompetitive N-methyl D-aspartate (NMDA) receptor antagonist, is widely used in pediatric clinical practice. The neuroprotective and neurotoxic effects of ketamine on brain neurons during development remain controversial. The reason may be related to the different concentrations of ketamine used in practice and the small range of concentrations used in previous studies. In this study, cultured hippocampal neurons were treated with ketamine in a wide range of concentrations to comprehensively observe the effects of different concentrations of ketamine on neurons. We demonstrated that low concentrations of ketamine (10 μM, 100 μM and 1000 μM) promoted neuronal survival (p < 0.05) and reduced neuronal apoptosis (p < 0.05) compared with those of the control group. High concentrations of ketamine (2000 μM, 2500 μM and 3000 μM) reduced neuronal survival (p < 0.05) and promoted neuronal apoptosis (p < 0.05). The p38 MAPK inhibitor SB203580 reduced neuronal apoptosis induced by high concentrations of ketamine (2500 μM) (p < 0.05). Our findings indicate that ketamine exerts a dual effect on the apoptosis of primary cultured fetal rat hippocampal neurons in vitro and that the neurotoxic effects of ketamine are related to activation of the p38 MAPK signaling pathway.

NMDA Receptor Glycine Binding Site Modulators for Prevention and Treatment of Ketamine Use Disorder.

Ketamine offers a fast-acting approach to relieving treatment-resistant depression, but its abuse potential is an issue of concern. As ketamine is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) ion channel blocker, modulation of NMDAR might be an effective strategy to counteract the abuse liability of ketamine and even to treat ketamine use disorder. This study evaluated whether NMDAR modulators that act on glycine binding sites can decrease motivation to obtain ketamine and reduce reinstatement to ketamine-seeking behavior. Two NMDAR modulators, D-serine and sarcosine were examined. Male Sprague-Dawley rats underwent training to acquire the ability to self-administer ketamine. The motivation to self-administer ketamine or sucrose pellets was examined under a progressive ratio (PR) schedule. The reinstatement of ketamine-seeking and sucrose pellet-seeking behaviors were assessed after extinction. The results showed that both D-serine and sarcosine significantly decreased the breakpoints for ketamine and prevented reinstatement of ketamine seeking. However, these modulators did not alter motivated behavior for sucrose pellets, the ability of the cue and sucrose pellets to reinstate sucrose-seeking behavior or spontaneous locomotor activity. These findings indicate that two NMDAR modulators can specifically reduce the measures of motivation and relapse for ketamine in rats, suggesting that targeting the glycine binding site of the NMDAR is a promising approach for preventing and treating ketamine use disorder.

Unsubstantiated use of Selective serotonin reuptake inhibitors as an alternative for the treatment of depression

Unsubstantiated use of Selective serotonin reuptake inhibitors as an alternative for the treatment of depression

Antidepressant-like effect of CP-101,606: Evidence of mTOR pathway activation

BackgroundAs a non-competitive N-methyl d-aspartate receptor antagonist, ketamine exerts rapid-onset and long-lasting antidepressant effects on depression, but some side effects limit its use. To identify a safer compound that may provide similar antidepressant effects, here we investigated whether CP-101,606, a selective NR2B receptor inhibitor, provides similar antidepressant effects and explored its underlying mechanisms. MethodsTo mimic depressive-like behavior, mice were subjected to chronic unpredictable mild stress (CUMS) for 21 days. Mice were treated with CP-101,606 at 10, 20, and 40 mg/kg doses for 7, 14, and 21 days, respectively, followed by a sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST). Western blot analysis was performed on several targets (mTOR, p-mTOR, p70S6K, p-p70S6K, PSD-95, and GluA1), along with immunohistochemistry (GluA1) and immunofluorescence (p-mTOR) assays, using hippocampal tissue. ResultsCP-101,606 at 20 and 40 mg/kg doses for 7 and 14 days and fluoxetine 10 mg/kg and CP-101606 20 mg/kg for 21 days ameliorated depression-like behaviors in the SPT, TST, and FST. The effects of CP-101,606 were associated with a reversal of the CUMS-induced decrease in mTOR (Ser2448) and p70S6K (Thr389) phosphorylation and increasing PSD95 and GluA1 synthesis in the hippocampus. ConclusionsOur results demonstrate that CP-101,606 produces antidepressant effects in CUMS mice, which may be mediated by mTOR signaling cascade upregulation. Our findings suggest the possible utility of CP-101,606 as a treatment for depression.

Effects of Memantine on the Spontaneous Firing Frequency of Hippocampal CA1 Pyramidal Neurons in Intact and Alzheimer Rat Model: An Electrophysiological Study.

Memantine (MEM) is a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically used for the treatment of Alzheimer disease (AD) in mild to severe conditions. The present study was conducted to investigate the effects of memantine on the spontaneous firing frequency of CA1 pyramidal neurons in rats caused by an electrical lesion of Nucleus Basalis Magnocellularis (NBM). Then, this model of AD rats was compared with the intact adult male rats. In this study, adult male rats were divided into two groups. Group I (lesion of NBM, n=53) includes the following subgroups: lesion+saline, sham+saline, lesion+MEM 5 mg/kg, lesion+MEM 10 mg/kg, and lesion+MEM 20mg/kg. Group II (intact, n=48) includes the following subgroups: intact+saline, intact+MEM 3mg/kg, intact+MEM 5mg/kg, and intact+MEM 10mg/kg. Extracellular single-unit recording (15 min baseline+105 min after MEM or saline) was performed under urethane-anesthetized rats. The results showed that the mean frequency of CA1 pyramidal neurons after saline in the lesion+saline (P<0.001) group significantly decreases compared with the intact+saline and sham+saline groups. In addition, after saline and memantine, the mean frequency of CA1 pyramidal neurons in the lesion+MEM 10 mg/kg (P<0.01) and lesion+MEM 20 mg/kg (P<0.001) groups significantly increased compared with the lesion+saline group. Also, the mean frequencies of CA1 pyramidal neurons in the intact+MEM 10 mg/kg (P<0.001) group significantly decreased compared with the intact+saline group. Results showed that memantine increases the electrical activity of CA1 pyramidal neurons in a rat model of AD. Furthermore, in the intact adult male rats, the low-dose memantine, contrary to high dose, does not decrease the electrical activity of CA1 pyramidal neurons.

Ketamine and Its Emergence in the Field of Neurology.

The quest for a safe and effective anesthetic medication in the mid-20th century led to the discovery of CI-581, which was later named ketamine. Ketamine was labeled a “dissociative anesthetic” due to the state of sensory deprivation that it induces in the subjects receiving it. Although it enjoyed widespread use at the beginning of the Vietnam war, its use rapidly waned due to its psychedelic effect and it became more popular as a recreational drug, and in the field of veterinary medicine. However, as we gained more knowledge about its multiple sites of action, it has reemerged as a useful anesthetic/analgesic agent. In the last decade, the field of neurology has witnessed the growing use of ketamine for the treatment of several neurological conditions including migraine, status epilepticus, stroke, and traumatic brain injury (TBI). Ketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. The binding of ketamine to NMDA receptors leads to decreased frequency and duration of Ca+2 channel opening and thus inhibits glutaminergic transmission. This mechanism has proven to be neuroprotective in several neurological conditions. Ketamine does not increase intracranial pressure (ICP), and it maintains cerebral perfusion pressure (CPP) by increasing cerebral blood flow. Ketamine has also been shown to inhibit massive slow waves of neurological depolarizations called cortical spreading depolarizations (CSD), usually seen during acute neurological injury and are responsible for further neurological deterioration. Unlike other anesthetic agents, ketamine does not cause cardiac or respiratory suppression. All these favorable mechanisms and cerebral/hemodynamic actions have led to increased interest among clinicians and researchers regarding the novel uses of ketamine. This review will focus on the use of ketamine for various neurological indications.

Chronic oral olanzapine treatment but not haloperidol decreases [3H] MK-801 binding in the rat brain Independent of dietary conditions

Haloperidol and olanzapine are first and second-generation antipsychotic (neuroleptic) medications approved to treat schizophrenia. Glutamate signaling is known to play an important role in the manifestation of schizophrenia symptoms, as phencyclidine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, replicates and exasperates these symptoms. While initial reports show that neuroleptic treatments can impact aspects of NMDAR expression, there is little attention on the interaction between neuroleptics and dietary conditions. Thus, we examined the impact of chronic haloperidol and olanzapine treatment under both normal and high-fat dietary conditions on NMDAR expression. Adult male rats were treated for 28-days with either oral vehicle, haloperidol (1.5 mg/kg), or olanzapine (10 mg/kg), and fed either a standard control diet or a high-fat diet. In-vitro receptor autoradiography binding was performed using [3H] MK-801 as a measure of NMDAR expression. Results showed that olanzapine, irrespective of the diet, significantly decreased [3H] MK-801 binding within the cingulate cortex, substantia nigra, insular cortex, piriform cortex, ectorhinal cortex and perirhinal cortex, the forelimb region of the somatosensory cortex, and all quadrants of the caudate-putamen. In contrast, haloperidol treatment did not impact [3H] MK-801 binding, and we also report no effect of diet on [3H] MK-801 binding. These data suggest that the effects seen in olanzapine treatment are not mediated by diet, nor does a 28-day chronic high-fat diet alter [3H] MK-801 binding. Furthermore, these data also importantly support that combined consumption of a high-fat diet and pharmacological treatments are not immediately detrimental to NMDARs and contribute to the expansive literature of precision medicine.

Ketamine as a Novel Psychopharmacotherapy for Eating Disorders: Evidence and Future Directions

Eating disorders (EDs) are serious, life-threatening psychiatric conditions associated with physical and psychosocial impairment, as well as high morbidity and mortality. Given the chronic refractory nature of EDs and the paucity of evidence-based treatments, there is a pressing need to identify novel approaches for this population. The noncompetitive N-methyl-D-aspartate receptor (NMDAr) antagonist, ketamine, has recently been approved for treatment-resistant depression, exerting rapid and robust antidepressant effects. It is now being investigated for several new indications, including obsessive–compulsive, post-traumatic, and substance use disorder, and shows transdiagnostic potential for EDs, particularly among clinical nonresponders. Hence, the aim of this review is to examine contemporary findings on the treatment of EDs with ketamine, whether used as a primary, adjunctive, or combination psychopharmacotherapy. Avenues for future research are also discussed. Overall, results are encouraging and point to therapeutic value; however, are limited to case series and reports on anorexia nervosa. Further empirical research is thus needed to explore ketamine efficacy across ED subgroups, establish safety profiles and optimize dosing, and develop theory-driven, targeted treatment strategies at the individual patient level.

Activity-State Dependent Reversal of Ketamine-Induced Resting State EEG Effects by Clozapine and Naltrexone in the Freely Moving Rat.

Ketamine is a non-competitive N-Methyl-D-aspartate receptor (NMDAR) antagonist used in the clinic to initiate and maintain anaesthesia; it induces dissociative states and has emerged as a breakthrough therapy for major depressive disorder. Using local field potential recordings in freely moving rats, we studied resting state EEG profiles induced by co-administering ketamine with either: clozapine, a highly efficacious antipsychotic; or naltrexone, an opioid receptor antagonist reported to block the acute antidepressant effects of ketamine. As human electroencephalography (EEG) is predominantly recorded in a passive state, head-mounted accelerometers were used with rats to determine active and passive states at a high temporal resolution to offer the highest translatability. In general, pharmacological effects for the three drugs were more pronounced in (or restricted to) the passive state. Specifically, during inactive periods clozapine induced increases in delta (0.1–4 Hz), gamma (30–60 Hz) and higher frequencies (>100 Hz). Importantly, it reversed the ketamine-induced reduction in low beta power (10–20 Hz) and potentiated ketamine-induced increases in gamma and high frequency oscillations (130–160 Hz). Naltrexone inhibited frequencies above 50 Hz and significantly reduced the ketamine-induced increase in high frequency oscillations. However, some frequency band changes, such as clozapine-induced decreases in delta power, were only seen in locomoting rats. These results emphasise the potential in differentiating between activity states to capture drug effects and translate to human resting state EEG. Furthermore, the differential reversal of ketamine-induced EEG effects by clozapine and naltrexone may have implications for the understanding of psychotomimetic as well as rapid antidepressant effects of ketamine.

Magnesium sulphate within multimodal analgesia, pre-emptive, or preventive analgesia

BackgroundMagnesium (Mg) is a non-competitive N-methyl d-aspartate receptor antagonist with antinociceptive effects. Multimodal therapy is the optimal strategy for perioperative pain control to minimize the need for opioids. Inflammation caused by tissue trauma or direct nerve injury is responsible for the perioperative pain. The concept of “pre-emptive” analgesia, analgesic strategies administered prior to the stimulus, can modify the peripheral and central nervous system processing of noxious stimuli, thereby reducing central sensitization, hyperalgesia, and allodynia remains controversial. A more encompassing approach to the reduction of postoperative pain is the concept of “preventive” analgesia. The purpose of the study is to detect the proper use of MgSO4 as an analgesic being a non-competitive N-methyl d-aspartate (NMDA).ResultsThere is no statistically significant difference in the haemodynamic parameters, intraoperative (33% vs 20%) and postoperative requirement for analgesics 6.6% vs 10% among groups I and II, respectively. There is no significant difference in the numerical analogue scale, where 16 vs 17 patients with no pain, 12 vs 10 with mild pain, and 2 vs 3 with moderate pain in groups I and II, respectively.ConclusionThe use of MgSO4 in a bolus with or without infusion is comparable in the control of intraoperative and postoperative pain.

Implication of microglia in ketamine-induced long-term cognitive impairment in murine pups.

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is widely applicable to anesthesia, analgesia, and sedation. However, the function and mechanisms of ketamine in the long-term learning and memory function of neonatal mice are unclear. The present study aims to investigate whether long-term learning and memory function will be affected by multiple ketamine exposures in the early development period. The mRNA and protein levels were measured by RT-qPCR and western blot, respectively. The Morris Water Maze test was performed to assess spatial learning and memory. We identified that neonatal exposure to ketamine downsized the positive neurons for microtubule-associated protein doublecortin (DCX) and Ki67 in hippocampal dentate gyrus at the juvenile and late adolescence stages. Double-labeling tests demonstrated that the counts of Iba1+ cells and Ki67+ cells were pronouncedly diminished with exposure to ketamine. Further, qPCR assays to screen the key factors predisposing the populations and maturation of microglia exhibited remarkable decline of CX3CR1 mRNA levels in ketamine group versus the control group. The close relation of microglia to synaptic plasticity was depicted by the significantly downregulated synaptic plasticity-related proteins NR2B and PSD-95 subsequent to multiple exposures to ketamine. Finally, we found that both the protein and mRNA levels of BDNF were markedly decreased in ketamine group versus the control group. We found that multiple exposures to ketamine in neonatal mice lead to spatial learning and memory dysfunction. The alterations of microglial development and function are the possible mechanisms of long-term learning and memory impairment.

Ketamine: Neuroprotective or Neurotoxic?

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.

Therapeutic Potentials of Ketamine and Esketamine in Obsessive-Compulsive Disorder (OCD), Substance Use Disorders (SUD) and Eating Disorders (ED): A Review of the Current Literature.

The obsessive–compulsive spectrum refers to disorders drawn from several diagnostic categories that share core features related to obsessive–compulsive disorder (OCD), such as obsessive thoughts, compulsive behaviors and anxiety. Disorders that include these features can be grouped according to the focus of the symptoms, e.g., bodily preoccupation (i.e., eating disorders, ED) or impulse control (i.e., substance use disorders, SUD), and they exhibit intriguing similarities in phenomenology, etiology, pathophysiology, patient characteristics and clinical outcomes. The non-competitive N-methyl-D-aspartate receptor (NMDAr) antagonist ketamine has been indicated to produce remarkable results in patients with treatment-resistant depression, post-traumatic stress disorder and OCD in dozens of small studies accrued over the past decade, and it appears to be promising in the treatment of SUD and ED. However, despite many small studies, solid evidence for the benefits of its use in the treatment of OCD spectrum and addiction is still lacking. Thus, the aim of this perspective article is to examine the potential for ketamine and esketamine in treating OCD, ED and SUD, which all involve recurring and intrusive thoughts and generate associated compulsive behavior. A comprehensive and updated overview of the literature regarding the pharmacological mechanisms of action of both ketamine and esketamine, as well as their therapeutic advantages over current treatments, are provided in this paper. An electronic search was performed, including all papers published up to April 2021, using the following keywords (“ketamine” or “esketamine”) AND (“obsessive” OR “compulsive” OR “OCD” OR “SUD” OR “substance use disorder” OR “addiction” OR “craving” OR “eating” OR “anorexia”) NOT review NOT animal NOT “in vitro”, on the PubMed, Cochrane Library and Web of Science online databases. The review was conducted in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The use and efficacy of ketamine in SUD, ED and OCD is supported by glutamatergic neurotransmission dysregulation, which plays an important role in these conditions. Ketamine’s use is increasing, and preliminary data are optimistic. Further studies are needed in order to better clarify the many unknowns related to the use of both ketamine and esketamine in SUD, ED and OCD, and to understand their long-term effectiveness.

Ketamine Alters Functional Plasticity of Astroglia: An Implication for Antidepressant Effect.

Ketamine, a non-competitive N–methyl–d–aspartate receptor (NMDAR) antagonist, exerts a rapid, potent and long-lasting antidepressant effect, although the cellular and molecular mechanisms of this action are yet to be clarified. In addition to targeting neuronal NMDARs fundamental for synaptic transmission, ketamine also affects the function of astrocytes, the key homeostatic cells of the central nervous system that contribute to pathophysiology of major depressive disorder. Here, I review studies revealing that (sub)anesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]i) in astrocytes, attenuate stimulus-evoked astrocyte calcium signaling, which regulates exocytotic secretion of gliosignaling molecules, and stabilize the vesicle fusion pore in a narrow configuration, possibly hindering cargo discharge or vesicle recycling. Next, I discuss how ketamine affects astrocyte capacity to control extracellular K+ by reducing vesicular delivery of the inward rectifying potassium channel (Kir4.1) to the plasmalemma that reduces the surface density of Kir4.1. Modified astroglial K+ buffering impacts upon neuronal firing pattern as demonstrated in lateral habenula in a rat model of depression. Finally, I highlight the discovery that ketamine rapidly redistributes cholesterol in the astrocyte plasmalemma, which may alter the flux of cholesterol to neurons. This structural modification may further modulate a host of processes that synergistically contribute to ketamine’s rapid antidepressant action.

A key requirement for synaptic Reelin signaling in ketamine-mediated behavioral and synaptic action

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant action in some patients with treatment-resistant depression. However, recent data suggest that ∼50% of patients with treatment-resistant depression do not respond to ketamine. The factors that contribute to the nonresponsiveness to ketamine's antidepressant action remain unclear. Recent studies have reported a role for secreted glycoprotein Reelin in regulating pre- and postsynaptic function, which suggests that Reelin may be involved in ketamine's antidepressant action, although the premise has not been tested. Here, we investigated whether the disruption of Reelin-mediated synaptic signaling alters ketamine-triggered synaptic plasticity and behavioral effects. To this end, we used mouse models with genetic deletion of Reelin or apolipoprotein E receptor 2 (Apoer2), as well as pharmacological inhibition of their downstream effectors, Src family kinases (SFKs) or phosphoinositide 3-kinase. We found that disruption of Reelin, Apoer2, or SFKs blocks ketamine-driven behavioral changes and synaptic plasticity in the hippocampal CA1 region. Although ketamine administration did not affect tyrosine phosphorylation of DAB1, an adaptor protein linked to downstream signaling of Reelin, disruption of Apoer2 or SFKs impaired baseline NMDA receptor-mediated neurotransmission. These results suggest that maintenance of baseline NMDA receptor function by Reelin signaling may be a key permissive factor required for ketamine's antidepressant effects. Taken together, our results suggest that impairments in Reelin-Apoer2-SFK pathway components may in part underlie nonresponsiveness to ketamine's antidepressant action.

The effect of GABA-B receptors in the basolateral amygdala on passive avoidance memory impairment induced by MK-801 in rats

MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 μg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 μg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 μg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 μg/rat, baclofen at the doses of 0.001 and 0.01 μg/rat, and phaclofen at the doses of 0.001 and 0.01 μg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 μg/rat) and phaclofen (0.0001 μg/rat) restored the impairment effect of MK-801 (0.5 μg/rat) on memory. Also, both baclofen (0.0001 μg/rat) potentiated the impairment effect of MK-801 (0.125 μg/rat) and phaclofen (0.0001 μg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 μg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.

Hypomania associated with high dose ketamine treatment.

For more than 50 years, pharmacotherapy for major depressive disorder (MDD) has narrowly focused on enhancing monoaminergic neurotransmission resulting in more than 30 FDA- approved treatments. In contrast, the glutamatergic, non-competitive N-methyl D-aspartate (NMDA) receptor antagonist ketamine has been "repurposed" as a rapid acting antidepressant1 ; the enantiomer S-ketamine, or esketamine, is now FDA-approved for treatment resistant unipolar depression (TRD).

Ketamine Action on Astrocytes Provides New Insights into Rapid Antidepressant Mechanisms.

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts rapid, potent and long-lasting antidepressant effect already after a single administration of a low dose into depressed individuals. Apart from targeting neuronal NMDARs essential for synaptic transmission, ketamine also interacts with astrocytes, the principal homoeostatic cells of the central nervous system. The cellular mechanisms underlying astrocyte-based rapid antidepressant effect are incompletely understood. Here we overview recent data that describe ketamine-dependent changes in astrocyte cytosolic cAMP activity ([cAMP]i) and ketamine-induced modifications of stimulus-evoked Ca2+ signalling. The latter regulates exocytotic release of gliosignalling molecules and stabilizes the vesicle fusion pore in a narrow configuration that obstructs cargo discharge or vesicle membrane recycling. Ketamine also instigates rapid redistribution of cholesterol in the astrocyte plasmalemma that may alter flux of cholesterol to neurones, where it is required for changes in synaptic plasticity. Finally, ketamine attenuates mobility of vesicles carrying the inward rectifying potassium channel (Kir4.1) and reduces the surface density of Kir4.1 channels that control extracellular K+ concentration, which tunes the pattern of action potential firing in neurones of lateral habenula as demonstrated in a rat model of depression. Thus, diverse, but not mutually exclusive, mechanisms act synergistically to evoke changes in synaptic plasticity leading to sustained strengthening of excitatory synapses necessary for rapid antidepressant effect of ketamine.

Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice.

Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine’s ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. Combined with what is already known about ketamine’s action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine’s abuse potential but have superior efficacy in treating depression.

Memantine Derivatives as Multitarget Agents in Alzheimer's Disease.

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors.