Effects of memantine,an NMDA receptor antagonist,on place preference conditioned with drug and nondrug reinforcers in mice

Antagonists of the N-methyl-D-aspartate (NMDA) receptor complex have been shown to inhibit the expression of place preferences conditioned with several drugs that are abused by humans, which suggests that this class of compounds may be beneficial in the treatment of substance dependence. Therefore it is important to assess the specificity of this effect, of whether inhibitory effects of NMDA receptor antagonists on conditioned drug stimuli generalize to behaviors produced by nondrug reinforcers. The present study was designed to compare the effects of the NMDA receptor channel blocker, memantine, on the expression of place preferences conditioned with: (1) consumption of regular laboratory food; (2) sexual encounters with females; and (3) injection of morphine (10 mg/kg) in adult male Swiss mice. For all three experiments reported here, unconditioned stimuli (food, receptive female or morphine) were presented before the exposures to the "to-be-conditioned" environments. Significant place preferences developed as a result of explicit pairings of the environmental context and food consumption, sexual encounter and morphine administration. Memantine (7.5 mg/kg, given prior to the post-conditioning test) inhibited the expression of place preferences conditioned with morphine and sexual encounter, but had no effects in food-conditioned mice. These findings suggest that the effects of NMDA receptor blockade may not be limited to drug-reinforced behaviors.     

The NMDA receptor channel blocker memantine and opioid receptor antagonist naltrexone inhibit the saccharin deprivation effect in rats

Several drugs, such as N-methyl-D-aspartate (NMDA) receptor channel blockers (memantine), naltrexone (but not naloxone) and acamprosate, have previously been reported to attenuate the expression of the alcohol deprivation effect, a phenomenon seen as an increase in post-deprivation alcohol consumption. The present study aimed to evaluate the effects of these drugs on the development and expression of the saccharin deprivation effect in adult male Wistar rats. Memantine (13 mg/kg per day) and naltrexone (5 mg/kg, twice daily), but not naloxone (24 mg/kg per day) or acamprosate (200 mg/kg, twice daily), prevented the increase in the consumption of saccharin after a 1-week deprivation from free-choice, unlimited access to saccharin (0.1%, w/v). Taken together with the results of previous studies, these results suggest that naltrexone and memantine attenuate the expression of both the alcohol and saccharin deprivation effects.     

Effects of the NMDA antagonist memantine on human methamphetamine discrimination

Abstract Rationale. The discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. Objective. This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Methods. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Results. Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. Conclusion. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects. Electronic Publication     

The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans

RATIONALE: The serotonin system has an important role in the modulation of several processes relevant to psychiatry such as anxiety, affect, aggression, and drug abuse. This review summarizes the recent progress in elucidating the function of the serotonergic system using knockout mice. This review while not exhaustive, highlights recent findings of relevance to psychopharmacology. OBJECTIVES: To familiarize the reader with the technique and the findings from serotonergic knockout mice. METHODS: Information included in this review was drawn from our own experience in this field and relevant publications from other investigators. RESULTS: We have focused on three main themes that have emerged from studies with mice bearing single-gene mutations of serotonergic genes: anxiety, aggression, and drug abuse. Mice lacking the 5-HT1A have been found to be more anxious in several behavioral paradigms. Elevated levels of aggression have been reported in mice lacking the monoamine oxidase A and the 5-HT1B receptor genes. The mice lacking the 5-HT1B receptor have also been reported to exhibit an increased vulnerability to cocaine. The molecular basis of this enhanced vulnerability has been linked to compensatory changes in the nucleus accumbens. These results and their correlation with pharmacological studies will be discussed. CONCLUSION: Mice lacking key components of the serotonin system have provided us with important animal models of genetic vulnerability to conditions such as anxiety disorders, aggression, and drug abuse. Ongoing research with these mice may help elucidate the mechanistic functioning of this complex system.     

Caffeine withdrawal syndrome in social interaction test in mice: effects of the NMDA receptor channel blockers, memantine and neramexane

Antagonists acting at N-methyl-D-aspartate (NMDA) receptors have been demonstrated repeatedly to attenuate the expression of drug and alcohol withdrawal syndromes. The present study aimed to evaluate the effects of NMDA receptor blockade on the expression of behavioural signs of caffeine withdrawal syndrome, assessed using the social interaction paradigm. Adult male Swiss mice were treated with increasing doses of caffeine (40-100 mg/kg, i.p., twice daily) for 8 days. Twenty-four hours after the last injection of caffeine, there were significant increases in duration and frequency of defensive behaviours, as well as decreased locomotor activity. These changes faded within 72 hours. Pretreatment with a single dose of caffeine (1 mg/kg; 24 h after the end of repeated caffeine administration and 30 min prior to the test) completely reversed these withdrawal-related changes. Separate groups of mice were treated i.p. with different doses of memantine (1, 3 or 10 mg/kg) or neramexane (MRZ 2/579; 1, 3 or 10 mg/kg) 24 h after the last caffeine injection. Both compounds dose-dependently reduced the expression of defensive behaviours while increasing motor activity. These data suggest that NMDA receptor blockade may counteract the acute behavioural effects of caffeine withdrawal.     

Effect of NMDA receptor antagonist on naloxone-precipitated withdrawal signs in cholestatic mice

The ability of NMDA antagonist MK-801 to block the expression of opioid-like withdrawal signs was examined in bile duct-ligated mice and the signs were compared with sham operated and unoperated animals. Administration of MK-801 (0/1 mg/kg), 10 min prior to naloxone challenge, significantly reduced the investigated withdrawal signs (jumping, diarrhoea, grooming and climbing) in bile duct-ligated animals. Chronic administration (five consecutive days) of MK-801 (0/1 mg/kg) also decreased all the withdrawal signs in the experimental animals. In an independent series of experiments, the effect of acute and chronic administration of MK-801 on tail-flick latency was investigated in bile duct-ligated animals. Pretreatment with the drug significantly decreased the antinociception induced by bile duct ligation in the mice. The results of this study support evidence for the involvement of the NMDA receptor in yopioidergic-dependent manifestations in a model of obstructive cholestasis. Copyright 2000 John Wiley & Sons, Ltd.     

Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice

The tail-flick test was used to investigate the effects of chronic administration of the N-methyl-D-aspartate (NMDA) receptor antagonists, dextromethorphan, memantine and MRZ 2/579, on the development and reversal of morphine tolerance in mice in three separate experiments. Experiment 1 investigated the effects of NMDA receptor antagonists on the development of tolerance. Morphine (10 mg/kg for 6 days, twice daily) produced a 5.9-fold rightward shift of the cumulative dose-response curves. Co-administration of dextromethorphan, memantine or MRZ 2/579 between tests 1 and 2 dose-dependently (5-10 mg/kg) inhibited the development of morphine tolerance. In experiment 2, in which the effects on the reversal were investigated, morphine-tolerant mice were treated b.i.d. for an additional 6 days (between tests 2 and 3) with vehicle+vehicle, NMDA receptor antagonist+vehicle, vehicle+morphine or NMDA receptor antagonist+morphine. Morphine-tolerant mice treated with vehicle+vehicle remained morphine tolerant, whereas this residual morphine tolerance was inhibited by administration of all three NMDA antagonists (each 10 mg/kg). Morphine-tolerant mice receiving vehicle+morphine injections demonstrated an unchanged degree of antinociceptive tolerance. In these mice, the co-administration of memantine and MRZ 2/579, but not dextromethorphan, resulted in the reversal of morphine tolerance. In experiment 3, memantine and MRZ 2/579 (10 mg/kg) inhibited the acute antinociceptive effect of morphine, but dextromethorphan did not. These data indicate that low-affinity, clinically available and/or therapeutically promising NMDA receptor antagonists may be used to inhibit ongoing morphine tolerance.     

Effects of the NMDA receptor channel blockers memantine and MRZ 2/579 on morphine withdrawal-facilitated aggression in mice

Rationale: Opioid withdrawal is known to facilitate aggressive behavior in laboratory rodents. Aggression develops as the somatic signs disappear and thus may reflect protracted withdrawal-related behavioral alterations. Antagonists acting at the NMDA receptor are known to attenuate the expression of morphine withdrawal syndrome in laboratory animals. Objective: The present study aimed to evaluate the effects of low-affinity NMDA receptor channel blockers (memantine and MRZ 2/579) on aggression facilitated by morphine withdrawal in mice. Methods: Significant increases in aggressive behavior were observed 48 h after repeated morphine administration (8 days, b.i.d., 10–80 mg/kg, SC) was discontinued. Separate groups of mice were treated intraperitoneally with vehicles or different doses of memantine (1, 3, 10 or 30 mg/kg) or MRZ 2/579 (1, 3 or 10 mg/kg) 48 h after the last morphine injection. Results: Both compounds dose-dependently reduced the expression of aggressive behavior while having no significant effect upon the intensity of non-aggressive social contacts. Memantine significantly diminished the occurrence of all recorded components of aggressive behavior (attacks/bites, threats, tail rattling) while MRZ 2/579 affected mainly the appetitive events of aggressive bursts (threats, tail rattling). For both compounds, anti-aggressive effects occurred at dose levels that did not produce motor impairment in the Rotarod test. Conclusions: Taken together with the evidence on the lack of selective anti-aggressive effects of these drugs in morphine-naive mice, attenuation of the aggression observed in the present study may be due to specific interaction with morphine withdrawal-triggered processes. Received: 2 May 1999 / Final version: 17 November 1999     

Effects of memantine, a non-competitive N-methyl-D-aspartate receptor antagonist, on genomic stability

Memantine is an aminoadamantane drug useful in neurodegenerative diseases, with beneficial effects on cognitive functions. Some studies have shown that memantine protects brain cells, thereby decreasing glutamate excitotoxicity. This study evaluated the genotoxic/antigenotoxic and mutagenic effects of memantine in CF-1 mice, following standardized protocols. Memantine was administered i.p. at 7.5, 15 or 30 mg/kg for three consecutive days. Blood and brain samples were collected to assess DNA damage using the alkaline comet assay. The mutagenic effect was assessed using the bone marrow micronucleus test. In addition, possible antioxidant effects were evaluated measuring the survival of Saccharomyces cerevisiae yeast strains [wild-type (WT) and isogenic mutants lacking superoxide dismutase] to cotreatment of memantine plus hydrogen peroxide. Memantine decreased DNA oxidative damage mainly in brain tissue. This antigenotoxic effect corroborated an increase observed in the survival of S. cerevisiae WT strain against hydrogen peroxide-induced damage. Furthermore, memantine did not increase the micronucleus frequency. The overall results indicate that memantine showed no mutagenic activity, did not cause DNA damage in the blood and brain tissues and showed antigenotoxic effects in brain tissue.     

Effects of the noncompetitive NMDA receptor antagonist MK-801 on classical eyeblink conditioning in mice

N-methyl-D-aspartate (NMDA) receptors are involved in synaptic plasticity and play a critical role in learning and memory. We investigated the effects of the noncompetitive NMDA receptor antagonist (+)MK-801 on classical eyeblink conditioning of mice, using various interstimulus intervals between the conditioned stimulus (CS) and unconditioned stimulus (US). A tone was used for the CS and a periorbital shock was used for the US. In the delay paradigm, in which the US coterminated with the CS or started immediately after CS offset, the effect of (+)MK-801 (0.1mg/kg, i.p.) was a slight impairment in the acquisition of the conditioned response (CR). During subsequent CS-alone trials, the responses of (+)MK-801-injected mice were extinguished as easily as those of saline-injected mice. In the trace paradigm, (+)MK-801 impaired acquisition of the CR with a trace interval of 250 ms more than it did with a trace interval of 100 ms, and more than in the delay paradigm. (+)MK-801 injected after acquisition of 250-ms trace conditioning did not impair expression or extinction of the CR. These results suggest that NMDA receptors are involved in acquisition of the CR during longer trace interval conditioning more than during shorter trace interval conditioning or delay conditioning, and that their contribution to extinction is much smaller than their contribution to acquisition in mouse eyeblink conditioning.     

Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond

Neuroprotective drugs tested in clinical trials, particularly those that block N-methyl-D-aspartate-sensitive glutamate receptors (NMDARs), have failed miserably in large part because of intolerable side effects. However, one such drug, memantine, was recently approved by the European Union and the US FDA for the treatment of dementia following our group's discovery of its clinically tolerated mechanism of action. Here, we review the molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca(2+) influx through the receptor's associated ion channel and consequent free-radical formation.     

The uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine prolongs spatial memory in a rat delayed radial-arm maze memory task

In the present study, we evaluated the effects of memantine in a delayed radial-arm maze rat task, consisting of an acquisition phase followed 18 h later by a win-shift retrieval test. When administered 20 min before acquisition, memantine elicited an inverted U-shape dose-response relationship, with low doses (0.3 and 0.56 mg/kg) reducing the number of errors committed during the retrieval test, while high doses (3 and 10 mg/kg) disrupted maze running. Memantine given immediately after acquisition or 20 min before retrieval failed to affect performance. Co-administration of subthreshold doses of memantine with either the CB(1) receptor antagonist rimonabant or the acetylcholine esterase inhibitor donepezil failed to enhance performance. Thus, low doses of memantine enhance acquisition processes that lead to prolonged spatial memory.     

Enhancement of morphine actions in morphine-naive and morphine-tolerant mice by LY 235959, a competitive antagonist of the NMDA receptor

• 1.1. The effects of LY 235959, a competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, on the analgesic and hypothermic actions of morphine, were determined in nontolerant and morphine-tolerant mice.
• 2.2. LY 235959 enhanced the analgesic and hypothermic action of morphine in nontolerant mice.
• 3.3. LY 235959 also enhanced the analgesic and hypothermic actions of morphine in morphine-tolerant mice. LY 235959, injected before saline injection, had no effect on the antinociception or the body temperature.
• 4.4. It is concluded that competitive antagonism of the NMDA receptor enhances the pharmacologic actions of morphine both in morphine-naive and morphine-tolerant mice and that these actions differ from the noncompetitive antagonism of the NMDA receptors.

     

Effects of the NMDA receptor antagonist ketamine in electrically induced A delta-fiber pain

OBJECTIVES: Both ketamine and pethidine have previously been found to have analgesic effects in experimentally induced C-fiber pain. The aim of the present study was to examine the effects of ketamine and pethidine in A delta-fiber-mediated pain induced by electrical tooth stimulation. METHODS: In this double-blind crossover study, an upper right central incisor was stimulated by a Bofors electrical stimulator before and after the intravenous administration of drugs. According to a randomized protocol and with a one-week wash-out period, 9 healthy female volunteers were given either racemic ketamine 0.3 mg/kg or pethidine 0.7 mg/kg, and 11 participants were given (R)-ketamine 0.5 mg/kg or (S)-ketamine 0.15 mg/kg. Pain thresholds were registered by an amperemeter on the stimulator. Drug-induced side effects were registered by use of a standardized questionnaire and visual analog scales. RESULTS: Both ketamine and pethidine gave significant but short-lasting increases in pain thresholds compared to no medication. The participants reported more pronounced mental side effects after ketamine injection. A comparison of (R)- and (S)-ketamine revealed no statistical difference in the effect on pain thresholds of the two enantiomers at the present doses, but 7 out of 11 participants reported to have fewer and less pronounced side effects from (R)-ketamine than from (S)-ketamine. CONCLUSIONS: Ketamine and pethidine have only a marginal effect on pain thresholds in electrically induced A delta-fiber-mediated tooth pulp pain, in contrast to the analgesic effects previously found in experimental and postoperative C-fiber-mediated pain. The ketamine enantiomers at the doses used in this study showed equal analgesic properties but different side effect profiles.     

Enhancement of long-term spatial memory in adult rats by the noncompetitive NMDA receptor antagonists, memantine and neramexane

Memantine and neramexane are noncompetitive NMDA receptor antagonists which have been investigated for their promising effects in aiding memory in people with dementia. Memantine is approved for the treatment of Alzheimer's disease, and neramexane is currently under development for this indication. Therefore, the present study provided a comparative assessment of the effects of equimolar doses of memantine and neramexane on spatial (hippocampus-dependent) memory. Adult male rats were given only 3 training trials to learn the location of a hidden platform in a water maze. In control (vehicle-injected) rats, this minimal amount of training produced intact short-term (15 min), but poor long-term (24 h), memory. Pre-training administration of memantine or neramexane produced a dose-dependent enhancement of long-term memory. Pharmacokinetic experiments with equimolar doses of both agents indicated that lower plasma levels of neramexane were more effective than memantine at enhancing memory. The effective doses of both agents in the current study produced plasma levels (and extrapolated brain CSF levels) within a range of activity at NMDA receptors and plasma levels seen in patients with Alzheimer's disease. These findings provide support for the use of neramexane as a pharmacological intervention in the treatment of dementia.     

Structure-function relationships of the NMDA receptor antagonist conantokin peptides

The three members of the conantokin peptide family identified to date are conantokin(con)-G, -T and -R. Their defining attributes include a high relative content of gamma-carboxyglutamic acid (Gla), N-terminal sequence identity, as well as considerable overall sequence homology, and antagonism of the N-methyl-D-aspartate receptor (NMDAR). As promising templates for the design of neuroprotective agents, a thorough evaluation of structure-function relationships in these peptides will be invaluable in aiding rational drug modeling. To this end, a comprehensive assessment of the contributions of individual residues to conantokin structure and function is required. The current review summarizes recent efforts in this area, and also includes the effects of peptide length, as well as structural-stabilization and -destabilization on the structural and inhibitory profiles of an extensive panel ofconantokin derivatives.     

Clinically available NMDA antagonist, memantine, attenuates tolerance to analgesic effects of morphine in a mouse tail flick test

Converging lines of evidence indicate that N-methyl-D-aspartate (NMDA) receptor antagonists attenuate the development of morphine tolerance tested in antinociception assays in rodents. The present study extends these findings to the effects of clinically available NMDA receptor antagonist, memantine. Male Albino Swiss mice were tested for analgesia using the tail-flick apparatus. Preliminary experiment was designed to find out the optimal dose of morphine and the number of injections that would produce tolerance to its analgesic effects. In the main experiment, during the development of tolerance period (6 days), mice received 10 mg/kg sc b.i.d. morphine injections in the animal room (non-associative tolerance). This treatment resulted in 5.8 fold rightward shift of morphine cumulative dose-response effect from 3.39 mg/kg on day 1 to 16.19 mg/kg on day 8 of the experiment. Memantine pretreatment (5 and 10 mg/kg, but not 2.5 mg/kg), given 30 min prior to each morphine dose during the development of tolerance period, inhibited the rightward shift of morphine cumulative dose-response curve. Thus, pretreatment with memantine at doses of 2.5, 5 and 10 mg/kg resulted in ED50 values of 12.13, 4.74 and 1.95 mg/kg, respectively, corresponding to 3.35, 1.02 and 0.94 fold changes. These data indicate that low affinity, clinically available NMDA receptor antagonist, memantine, may be used to inhibit the development of morphine tolerance.     

Minocycline attenuates hyperlocomotion and prepulse inhibition deficits in mice after administration of the NMDA receptor antagonist dizocilpine.

The present study was undertaken to examine whether the second generation antibiotic drug minocycline attenuates behavioral changes (eg, acute hyperlocomotion and prepulse inhibition (PPI) deficits) in mice after the administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-MK-801 (dizocilpine). Dizocilpine (0.1 mg/kg)-induced hyperlocomotion was significantly attenuated by pretreatment with minocycline (40 mg/kg). Furthermore, the PPI deficits after a single administration of dizocilpine (0.1 mg/kg) were attenuated by pretreatment with minocycline (10, 20, or 40 mg/kg), in a dose-dependent manner. Moreover, in vivo microdialysis study in the free-moving mice revealed that pretreatment with minocycline (40 mg/kg, i.p.) significantly attenuated the increase of extracellular dopamine (DA) levels in the frontal cortex and striatum after administration of dizocilpine (0.1 mg/kg), suggesting that the inhibition of dizocilpine-induced DA release by minocycline may, at least in part, be implicated in the mechanism of action of minocycline with respect to dizocilpine-induced behavioral changes in mice. These findings suggest that minocycline could attenuate behavioral changes in mice after the administration of the NMDA receptor antagonist dizocilpine. Therefore, it is possible that minocycline would be a potential therapeutic drug for schizophrenia.