Non-competitive NMDA Receptor Antagonist Research Articles

Ketamine-Induced Biliary Ductal Dilatation: A Case Report and Review of Literature

Introduction: Ketamine is a noncompetitive NMDA receptor antagonist that is still widely used as a dissociative anesthetic agent as well as a recreational hallucinogenic drug. There is now emerging evidence that ketamine is associated with GI symptoms, abnormal liver function tests, and biliary tract abnormalities. A 19-year-old female presented with abdominal pain, hematuria, and fever for 1 day. She denied any history of drug abuse. Vital signs were within normal limits and physical revealed tenderness on the lower abdominal quadrants. Labs were significant for a ALP of 559 and ALT of 124. CT showed b/l hydroureteronephrosis as well as extra- and intrahepatic ductal dilatation up to 11 mm. Patient was started on antibiotics for UTI, and MRCP confirmed the biliary dilatation. Two unlabeled vials were found in her belongings and she admitted to using ketamine for many months.Table 1Patient progressed well and was discharged with follow-up with an addiction specialist. A literature search revealed 10 other cases with limited cases in the United States. The exact mechanism remains unknown, although it has been postulated that it is due to either direct actions on the biliary smooth muscles or central action. Studies have shown that ketamine dilates cerebral arteries by acting as a calcium antagonist. It is possible that this effect also extends to the biliary tree smooth muscle, thus causing biliary dilatation. Another hypothesis includes the dorsal motor nucleus of vagus (DMV), which has efferent fibers that project to the gallbladder. Injection of NMDA into the DMV increases gallbladder motility and its effect can be abolished following the application of ketamine in animal studies. These manifestations may be fully reversible with abstinence despite a number of the reported cases having ERCP performed. Clinicians should be aware of biliary abnormalities as a possible consequence of ketamine, especially in light of increased prevalence of ketamine abuse and its emerging role as an adjunct to opioids in cancer patients.

P.1.a.010 Brain oscillatory patterns in 22q11 transgenic mice model. Interaction with non-competitive NMDA receptor antagonists

P.1.a.010 Brain oscillatory patterns in 22q11 transgenic mice model. Interaction with non-competitive NMDA receptor antagonists

Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function

Ketamine is a non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonist of interest in neuropsychiatry. In the present studies, we examined the effects of subanesthetic, low micromolar ketamine on excitatory postsynaptic potentials (EPSPs), population spikes (PSs) and synaptic plasticity in the CA1 region of rat hippocampal slices. Ketamine acutely inhibited NMDAR-mediated synaptic responses with half-maximal effects near 10 μM. When administered for 15–30 min at 1–10 μM, ketamine had no effect on baseline dendritic AMPA receptor-mediated EPSPs, but persistently enhanced somatic EPSPs in the pyramidal cell body layer and augmented PS firing. Acute low micromolar ketamine also had no effect on the induction of long-term potentiation (LTP) but blocked long-term depression (LTD). Following 30 min administration of 1–10 μM ketamine, however, a slowly developing and persistent form of LTP inhibition was observed that took two hours following ketamine washout to become manifest. This LTP inhibition did not result from prolonged or enhanced NMDAR inhibition during drug washout. Effects of low ketamine on somatic EPSPs and LTP were not mimicked by a high ketamine concentration that completely inhibited NMDARs, and both of these effects were blocked by co-administration of low ketamine with a low concentration of the competitive NMDAR antagonist, 2-amino-5-phosphonovalerate or inhibitors of nitric oxide synthase. These results indicate that concentrations of ketamine relevant to psychotropic and psychotomimetic effects have complex metaplastic effects on hippocampal function that involve activation of unblocked NMDARs during ketamine exposure.

Effects of an α5GABAA inverse agonist on MK-801-induced learning deficits in an incremental repeated acquisition task.

N-methyl-D-aspartate receptors (NMDARs) are essential for several kinds of synaptic plasticity and play a critical role in learning and memory. Deficits in NMDAR functioning may be partially responsible for the learning and memory deficits associated with aging and numerous diseases. Administration of MK-801, a noncompetitive NMDAR antagonist, is commonly used as a preclinical model of NMDAR dysfunction. The objective of this study was to assess the effects of α5GABAA receptor inhibition on learning deficits in the incremental repeated acquisition (IRA) task induced by acute MK-801 administration. The IRA task, commonly used to examine factors that affect learning, begins with a single response and increments to progressively longer chains throughout a single session as behavior meets preset criteria. MK-801 (0.03-0.5 mg/kg, intraperitoneally), administered 10 min pretesting, produced a significant dose-dependent decrease in measures of IRA performance at doses greater than or equal to 0.25 mg/kg. The MK-801-induced deficit was attenuated after treatment with an α5GABAA receptor inverse agonist, L-655,708 (1 mg/kg, intraperitoneally). The present study provides the focus for, and supports the feasibility of, further in-depth definitive studies examining α5GABAA receptor inhibition as a suitable candidate for the attenuation of NMDAR-related deficits.

Chronic administration of antipsychotics attenuates ongoing and ketamine-induced increases in cortical γ oscillations.

Noncompetitive N-methyl-d-aspartate receptor (NMDAr) antagonists can elicit many of the symptoms observed in schizophrenia in healthy humans, and induce a behavioural phenotype in animals relevant to psychosis. These compounds also elevate the power and synchrony of gamma (γ) frequency (30-80Hz) neural oscillations. Acute doses of antipsychotic medications have been shown to reduce ongoing γ power and to inhibit NMDAr antagonist-mediated psychosis-like behaviour in rodents. This study aimed to investigate how a chronic antipsychotic dosing regimen affects ongoing cortical γ oscillations, and the electrophysiological and behavioural responses induced by the NMDAr antagonist ketamine. Male Wistar rats were chronically treated with haloperidol (0.25mg/kg/d), clozapine (5mg/kg/d), LY379268 (0.3mg/kg/d) or vehicle for 28d, delivered by subcutaneous (s.c.) osmotic pumps. Weekly electrocorticogram (ECoG) recordings were acquired. On day 26, ketamine (5mg/kg, s.c.) was administered, and ECoG and locomotor activity were simultaneously measured. These results were compared with data generated previously following acute treatment with these antipsychotics. Sustained and significant decreases in ongoing γ power were observed during chronic administration of haloperidol (64%) or clozapine (43%), but not of LY379268 (2% increase), compared with vehicle. Acute ketamine injection concurrently increased γ power and locomotor activity in vehicle-treated rats, and these effects were attenuated in rats chronically treated with all three antipsychotics. The ability of haloperidol or clozapine to inhibit ketamine-induced elevation in γ power was not observed following acute administration of these drugs. These results indicate that modulation of γ power may be a useful biomarker of chronic antipsychotic efficacy.

Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms

Schizophrenic patients have been shown to exhibit abnormal cortical gamma band oscillation (GBO), which is thought to be related to the symptoms of schizophrenia, including cognitive impairment. Recently, non-competitive NMDA receptor (NMDAr) antagonists such as MK-801 and ketamine have been reported to increase the basal GBO power in rat cortical electroencephalograms. However, the mechanisms underlying the increase in basal GBO power induced by non-competitive NMDAr antagonists remain unclear. In the present study, we characterized the non-competitive NMDAr antagonists-increased GBO (30–80 Hz) power. MK-801 (0.05–0.2 mg/kg) increased the GBO power, exhibiting an inverted U-shape dose–response curve; at higher doses (0.3–1 mg/kg), the increase in GBO was reversed. The GBO power was closely correlated with the high-frequency oscillation (130–180 Hz) power following MK-801 administration, while the GBO power was inversely correlated with the increase in delta oscillation (0.5–4 Hz) power at higher doses. PCP (1.25–10 mg/kg) and ketamine (2.5–30 mg/kg) also exhibited the inverted U-shape dose-responses for the basal GBO power similar to MK-801. Interestingly, memantine (10–30 mg/kg) dose-dependently and potently increased the GBO power without remarkably affecting the other frequency band. In contrast, other psychotomimetics, such as methamphetamine (1–10 mg/kg) and DOI (0.5–2 mg/kg), did not induce noticeable changes in the basal GBO power even at doses that induce abnormal behaviors, indicating that the increase in GBO power induced by NMDAr antagonists is not necessarily attributed to psychotomimetic effects. In conclusion, the basal GBO power increase in response to non-competitive NMDAr antagonists may reflect the cortical hyperglutamatergic state through GABAergic disinhibition.

Rapid Antidepressant Action of Ketamine in Psychiatric Patients with Suicidality - a Case Series

Ketamine, a non-competitive NMDA receptor antagonist with rapid antidepressant action, is a novel approach in modulating glutamate receptors for management of treatment-resistant major depressive disorder. It clinically engenders meaningful advances in depression therapeutics. This case series highlights the role of low dose intravenous ketamine infusion i.e., 0.5 mg/kg dissolved in 100 ml normal saline and given over a period of 40 minutes in patients of depression who were contemplating suicide.

Pregnanolone Glutamate, a Novel Use-Dependent NMDA Receptor Inhibitor, Exerts Antidepressant-Like Properties in Animal Models.

A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders.Highlights: -3α5β-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like and antidepressant-like properties.

Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test

Opioid and glutamatergic receptors have a key role in depression following stress. In this study, we assessed opioid and glutamatergic receptors interaction with the depressant-like behavior of acute foot-shock stress in the mouse forced swimming test. Stress was induced by intermittent foot shock stimulation during 30min and swim periods were afterwards conducted by placing mice in separated glass cylinders filled with water for 6min. The immobility time during the last 4min of the test was considered. Acute foot-shock stress significantly increased the immobility time of mice compared to non-stressed control group (P≤0.01). Administration of non-selective opioid receptors antagonist, naltrexone (1 and 2mg/kg, i.p.), and the selective non-competitive NMDA receptor antagonist, MK-801 (0.05mg/kg, i.p.), and the selective serotonin reuptake inhibitor, fluoxetine (5mg/kg), significantly reduced the immobility time in stressed animals (P≤0.01). Lower doses of MK-801 (0.01mg/kg), naltrexone (0.3mg/kg), NMDA (75mg/kg) and morphine(5mg/kg) had no effect on foot-shock stressed mice. Combined treatment of sub-effective doses of naltrexone and MK-801 significantly showed an antidepressant-like effect (P≤0.001). On the other hand, co-administration of non-effective doses of NMDA and morphine with effective doses of naltrexone and MK-801 reversed the anti-immobility effect of these drugs. Taken together, we have for the first time demonstrated the possible role of opioid/NMDA receptors signaling in the depressant-like effect of foot-shock stress, and proposed the use of drugs that act like standard anti-depressants in stress-induced depression.

Inhibition of Acetylcholinesterase Modulates NMDA Receptor Antagonist Mediated Alterations in the Developing Brain

Exposure to N-methyl-d-aspartate (NMDA) receptor antagonists has been demonstrated to induce neurodegeneration in newborn rats. However, in clinical practice the use of NMDA receptor antagonists as anesthetics and sedatives cannot always be avoided. The present study investigated the effect of the indirect cholinergic agonist physostigmine on neurotrophin expression and the extracellular matrix during NMDA receptor antagonist induced injury to the immature rat brain. The aim was to investigate matrix metalloproteinase (MMP)-2 activity, as well as expression of tissue inhibitor of metalloproteinase (TIMP)-2 and brain-derived neurotrophic factor (BDNF) after co-administration of the non-competitive NMDA receptor antagonist MK801 (dizocilpine) and the acetylcholinesterase (AChE) inhibitor physostigmine. The AChE inhibitor physostigmine ameliorated the MK801-induced reduction of BDNF mRNA and protein levels, reduced MK801-triggered MMP-2 activity and prevented decreased TIMP-2 mRNA expression. Our results indicate that AChE inhibition may prevent newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways and by modulating the extracellular matrix.

N-methyl-d-aspartate Receptor Antagonist Ketamine Impairs Action-monitoring Activity in the Prefrontal Cortex

Failures in monitoring of self-generated actions are thought to underlie the positive symptoms in schizophrenia. It has been hypothesized that these deficits may be caused by a dysfunction of N-methyl-d-aspartate receptors (NMDARs). Here we recorded the activity of prefrontal neurons in monkeys performing an antisaccade task, while we administered a subanesthetic dose of the noncompetitive NMDAR antagonist ketamine. Many neurons discriminated between correct antisaccades and response errors in their postresponse activity. Ketamine increased the activity for the neurons' nonpreferred response, thereby decreasing the neurons' performance selectivity. Ketamine also affected the monkeys' behavior after an error, consistent with a deficit in error detection. The results show that NMDARs play an important role in action monitoring in primates. The decrease in performance selectivity of prefrontal neurons after ketamine can help to explain the deficits in action monitoring found in humans after ketamine administration and provides support for the hypothesis that an NMDAR dysfunction underlies self-monitoring deficits and psychotic symptoms in schizophrenia.

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern. This study examined abuse-related effects of ketamine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison. Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency-rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2-10.0mg/kg) and MK-801 (0.032-0.32mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2-20.0mg/kg/day) and acute cocaine (10.0mg/kg). Following acute administration, ketamine (3.2-10mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032-0.32mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0mg/kg cocaine facilitated ICSS. The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.

Ketamine, but not MK-801, produces antidepressant-like effects in rats responding on a differential-reinforcement-of-low-rate operant schedule

The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to produce rapid and lasting antidepressant effects in treatment-resistant patients with major depressive disorder and in preclinical behavioral assays. The present study sought to extend the preclinical antidepressant-like effects of ketamine using the differential-reinforcement-of-low-rate 72 s operant task in rats, as well as to determine whether the more selective and higher affinity NMDA receptor antagonist MK-801 produced antidepressant-like effects similar to those of ketamine. Ketamine, the NMDA receptor agonist N-methyl-D-aspartic acid, the tricyclic antidepressant imipramine, and the selective serotonin reuptake inhibitor fluoxetine all produced antidepressant-like effects by increasing the number of reinforcers, decreasing the number of responses, and producing a rightward shift in the peak location of the inter-response time distributions. Conversely, MK-801 and the dopamine receptor agonist D-amphetamine produced a psychostimulant-like effect by decreasing the number of reinforcers, increasing the number of responses, and producing a leftward shift in the peak location of the inter-response time distributions. Although a subeffective dose of ketamine attenuated the antidepressant-like effects of NMDA, a subeffective dose of NMDA did not alter the antidepressant-like effects of ketamine. These data indicate that ketamine and MK-801 produced dissociable effects in the differential-reinforcement-of-low-rate 72 s task, and further suggest that the underlying mechanisms responsible for the antidepressant effects of ketamine may be unique to ketamine and not shared by all NMDA receptor antagonists.

Blockade of MK-801-Induced Heat Shock Protein 72/73 in Rat Brain by Antipsychotic and Monoaminergic Agents Targeting D2, 5-HT<sub>1A</sub>, 5-HT<sub>2A</sub> and α<sub>1</sub>-Adrenergic Receptors

Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists can produce positive and negative symptomatology as well as impairment of cognitive function that closely resemble those present in schizophrenia. In rats, these drugs induce a behavioral syndrome (characterized by hyperlocomotion and stereotypies), an enhanced glutamatergic transmission in the medial prefrontal cortex, and damage to retrosplenial cortical neurons in adult rats, which was measured as the induction of the stress protein 72/73 kDa heat shock protein (Hsp72/73). In the present work, we have examined the existence of possible differences among different antipsychotic drugs in their capacity to block immunolabeling of Hsp72/73 in the retrosplenial cortex of the rat induced by the potent NMDA receptor antagonist, MK- 801. In addition, the effects of selective monoaminergic agents were also studied to delineate the particular receptors responsible for the actions of antipsychotic drugs. Pretreatment with clozapine, chlorpromazine, olanzapine, ziprasidone--and to a lesser extent haloperidol-reduced the formation of Hsp72/73 protein in the rat retrosplenial cortex after the administration of MK-801. In addition, antagonism at dopamine D2 (raclopride), 5-HT2 (M100907) and α1- adrenoceptors (prazosin) as well as agonism at 5-HT1A receptors (BAY x 3702) also diminished the MK-801-induced number of cells labeled with Hsp72/73. Each of these effects may contribute to antipsychotic action. The results suggest that the efficacy of atypical antipsychotic drugs in the clinic may result from a combined effect on 5-HT2, 5-HT1A and α1-adrenergic receptors added to the classical dopamine D2 receptor antagonism.

Effect of memantine on L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson’s disease

An increasing body of experimental evidence demonstrates that the glutamatergic system is involved in the genesis of l-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID). Indeed, the N-methyl-d-aspartate (NMDA) receptor antagonist amantadine is the only anti-dyskinetic compound used in patients, albeit with limited efficacy and side effects. In this study, we investigated the anti-dyskinetic properties of memantine, a non-competitive NMDA receptor antagonist in clinical use for the treatment of dementia, in the 6-hydroxy-dopamine (6-OHDA)-lesion rat model of Parkinson’s disease. For comparison, parallel experiments were also performed with amantadine.First, we investigated the acute effect of different doses of memantine (5, 10, 15 and 20mg/kg), and amantadine (10, 20, 40, 60mg/kg) on established dyskinesia induced by L-DOPA (6mg/kg plus benserazide). Results showed that both memantine and amantadine produced a significant reduction of LID. Afterward, drug-naïve and L-DOPA-primed 6-OHDA-lesioned rats were sub-chronically treated with daily injections of L-DOPA (6mg/kg plus benserazide) alone, or in combination with the effective doses of memantine, while amantadine was tested in already dyskinetic rats. Results showed that memantine significantly dampened dyskinesia in both drug-naïve and L-DOPA-primed rats, but only during the first few days of administration. In fact, the anti-dyskinetic effect of memantine was completely lost already at the fifth administration, indicating a rapid induction of tolerance. Interestingly, a 3-week washout period was not sufficient to restore the anti-dyskinetic effect of the drug. Similarly, amantadine was able to dampen already established dyskinesia only during the first day of administration. Moreover, memantine partially decreased the therapeutic effect of L-DOPA, as showed by the result of the stepping test. Finally, loss of the anti-dyskinetic effect of memantine was associated to increased synaptic GluN2A/GluN2B ratio at striatal synaptic membranes.Our results are in line with clinical observations suggesting that NMDA receptor blockade may only be transiently effective against LID in PD patients.

Impaired working memory by repeated neonatal MK-801 treatment is ameliorated by galantamine in adult rats

Early life blockade of the NMDA receptor by using MK-801, a non-competitive NMDA receptor antagonist, induces behavioral changes that mimic several features of schizophrenia. In the current study, we first examined the effects of neonatal MK-801 treatment in male Sprague-Dawley rats on locomotor activity, prepulse inhibition and spatial working memory in adolescence (postnatal day 35, PND35) and adulthood (PND63). Next, we investigated the effects of an acetylcholinesterase inhibitor, galantamine, on working memory deficits induced by MK-801 treatment. Rats were treated with either saline or MK-801 (0.25mg/kg twice daily) at PND 5–14, and the long-term behavioral effects were investigated. MK-801 treated rats showed moderate working memory impairments in adolescence but a pronounced deficit in adulthood. However, locomotion and prepulse inhibition at two life stages were not affected by this treatment. Systemic administration of galantamine (1mg/kg) 30min before each training session significantly improved neonatal MK-801-induced working memory deficits in adulthood. In conclusion, these results suggest that the neonatal MK-801 treatment-induced selective working memory deficit is related to a change in brain cholinergic systems.

Targeting of NMDA Receptors in the Treatment of Major Depression

Major depressive disorder (MDD) is a common, recurrent mental illness that affects millions of people worldwide. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays an important role in the neurobiology and treatment of this disease. Currently, the non-competitive NMDA receptor antagonist ketamine is considered as one of the most attractive candidate drugs in therapy of treatment-resistant depression. A recent study demonstrated ketamine's rapid antidepressant activity in patients with treatment-resistant MDD and bipolar disorder. The response rate for ketamine ranged from 25% to 85% at 24 hours post-infusion and from 14% to 70% at 72 hours post-infusion, with generally mild adverse effects. Based on the role of the NMDA receptor in depression, a number of therapeutic drugs which interact with this receptor have been developed. In this article, we reviewed recent findings concerning the role of glutamatergic signaling in the neurobiology of MDD and potential, novel therapeutic drugs, such as ketamine, memantine, AZD6765, traxoprodil, MK-0657, GLYX-13, NRX-1047, D-cycloserine, sarcosine, all of which target this system.

EPA-1261 – Rapid antidepressant effect of nmda antagonist and QEEG biomarker of sustained response

A series of clinical studies demonstrated that QEEG (quantitative electroencephalography) prefrontal theta cordance value decreases after one week of treatment in responders to antidepressants and precedes clinical improvement. Ketamine, a non-competitive antagonist of NMDA receptors, has a unique rapid antidepressant effect but its influence on QEEG measures is still unknown. To date wasn’t studied predictive value of cordance in response to single infusion of ketamine in depressive subjects. In a double-blind, cross-over, randomized, placebo-controlled experiment we studied the influence of ketamine (0.54 mg/kg) on theta cordance in a group of 27 right-handed hospitalized depressive patients on stable antidepressant medication. QEEG cordance values in theta frequency band were calculated according to UCLA algorithm. Responders (n=11) to ketamine in compare to non-responders (n=16) showed significant difference in cordance values at the end of ketamine infusion (Spearman, p= 0.039). The cordance decrease, measured between the end of infusion and next day, positively correlated with ketamine antidepressant response (MADRS decrease) fourth day after infusion (two-tailed Fisher's Exact test, df=1, p=0.0076) with NPV 90.9% (95% CI 64.3%-99.5%) and PPV 62.5% (95% CI 44.2%-68.4%). Our data indicate that ketamine infusion immediately induces similar changes as monoaminergic-based antidepressants do gradually after a series of downstream signalling steps. The reduction in theta prefrontal cordance could serve as a biomarker of sustained antidepressant response, a hypothesis that should be tested in larger depressive population.

EPA-1109 - Nmda receptor antagonists as analgesics in a rat model of visceral pain

Introduction N-methyl-D-aspartate (NMDA) receptors are ligand-gated receptor complexes that have been associated with learning and memory, pain transmission, depression, schizophrenia and neurodegenerative disorders. In these processes deficiency of magnesium has a significant role. Magnesium and MK-801, noncompetitive NMDA receptor antagonists, have been demonstrated analgesic efficacy against neuropathic pain, but there are no data about the effects of these compounds on visceral pain. Objective Comparison of the analgesic activity of NMDA antagonists against visceral inflammatory pain. AIM This study aimed at evaluating the effect of magnesium sulphate (MS) and MK-801 in writhing test in rats. Methods In writhing test, a model of visceral inflammatory pain, injection of diluted acetic acid into the peritoneal cavity of male Wistar rats induced pain. MS and MK-801 were given subcutaneously 15 min before the intraperitoneal injection of 0.7% acetic acid. Results MS at doses of 5 and 15 mg/kg did not affect the number of writhing in rats, but doses of 30 and 45 mg/kg significantly potentiated writhing 2.9 and 2.4 times, respectively. MK-801 (0.005 and 0.01 mg/kg) produced dose-dependent antinociception manifested as reduction in the number of writhing and the maximum antinociceptive activity was 61.3%. Conclusions MK-801 in the writhing test produced antinociception likely due to the inhibition of NMDA receptors. Effect of magnesium was different from MK-801. MS did not inhibit and even aggravated pain evoked by chemical stimuli in visceral pain test. The present results suggest that the MS may not be useful systemic analgesic in the therapy of visceral inflammatory pain.

Striking Similarities between Clinical and Biological Properties of Ketamine and Ethanol: Linking Antidepressant-After Effect and Burgeoning Addiction?

Ketamine is an old drug of abuse showing currently a new wave in its spread. Also, ketamine`s therapeutic quality is currently under strong observation, especially in terms of its value in the treatment of depression and suicidality. It`s a potential revolution in understanding the mechanisms of antidepressant treatment that single and repeated therapeutic administrations of sub-anesthetic ketamine doses are associated with a rapid and robust but transient antidepressant after-effect (ADE) in patients with treatment resistant major depression. There is increasing evidence that this ADE might result primarily from ketamine`s feature of being a non-competitive antagonist of glutamatergic N-methyl-D-aspartate (NMDA)-receptors embedded in synaptic membranes of neuronal cortico-limbic networks promoting an extracellular glutamate surge, thereby mediating changes in synaptic and cellular plasticity via local glutamate non-NMDA-receptors. Here, we focus on a couple of striking clinical and biological overlaps with ketamine and ethanol being a non-competitive antagonist of NMDA-receptors, too. Among them, a good portion is currently assumed to be specifically involved in both, the mechanisms of ADE (in the case of ketamine) and the development of addiction (in the case of ethanol). These overlaps are mainly addressed here in more detail, what may draw the reader in terms of the treatment of mood disorders to both, the possibility of a progressing transfer from ADE to addiction when repeatedly using therapeutic ketamine pulses, and on the other hand, a hypothesized therapeutic `antidepressant window´ of modest and cautious ethanol use in depressives, who are (still?) not addicted to ethanol. Of course, more frequent and intense use of ethanol or ketamine would prepare the brain to tolerance and dependence possibly using the same pathways.