Biomedical subjects

W Danysz

Publications and source records attributed to W Danysz.

At least 19 recordsLinked to original sources

PubMed2006

The role of group I metabotropic glutamate receptors in acquisition and expression of contextual and auditory fear conditioning in rats - a comparison.

Glutamatergic neurotransmission in the CNS plays a predominant role in learning and memory. While NMDA receptors have been extensively studied, less is known about the involvement of group I metabotropic glutamate receptors in this area. The purpose of the present study was to evaluate the contribution of mGluR1 and mGluR5 to both acquisition and expression of behaviours in contextual and auditory fear conditioning models. The effects of both receptor types were tested using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGluR1, and [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGluR5. Their effects on acquisition were compared to those of the NMDA receptor antagonist (+)MK-801, and the unselective muscarinic antagonist scopolamine, while diazepam and citalopram served as reference compounds in the expression experiments. EMQMCM (1.25 to 5mg/kg) impaired acquisition of contextual fear conditioning (CFC), but not auditory fear conditioning (AFC). Similarly, administration of MTEP during the acquisition phase impaired learning in CFC at doses of 2.5 to 10mg/kg, but was ineffective in AFC. When given before the retention test, both EMQMCM (1 and 3mg/kg) and MTEP (3mg/kg) impaired expression of CFC. In contrast, MTEP (2.5 and 5mg/kg) blocked the expression of AFC, while EMQMCM was ineffective. In conclusion, group I mGlu receptors are shown to be involved in the acquisition of hippocampus-dependent CFC, but not hippocampus-independent AFC. Unlike mGluR5, mGluR1 does not seem be involved in expression of AFC.

Acoustic Stimulation↗

PubMed2006

Analgesic effects of mGlu1 and mGlu5 receptor antagonists in the rat formalin test.

mGlu1 and mGlu5 receptors have been implicated in pain associated with inflammation. In the present study, the formalin test was used to measure sustained pain with components of tissue injury. The aims of the present study were to assess: (i) the role of mGlu1 and mGlu5 receptors in inflammatory pain using selective antagonist EMQMCM, 1.25-5 mg/kg, as the mGlu1 receptor antagonist, and MPEP or MTEP, 2.5-10 mg/kg, as mGlu5 receptor antagonist; (ii) the possible interaction between mGlu1 and mGlu5 receptor antagonists and morphine; and (iii) whether tolerance develops to the analgesic effects of these antagonists after prolonged treatment. EMQMCM, MTEP and MPEP significantly reduced the manifestation of both phases of formalin response. However, all these mGlu receptor antagonists did not affect the withdrawal latencies in a model of acute pain (Hargreaves test), which has a different underlying mechanism. In the present study, the suppressive effect on formalin-induced pain behaviour was much stronger when mGlu1 and mGlu5 receptor antagonists were co-injected compared to administration of a single antagonist, but this effect was not seen when mGlu receptor antagonist was co-administered with morphine. This is in contrast to the pronounced inhibitory effects after co-treatment with morphine and the uncompetitive NMDA receptor antagonist memantine. The present study also provides the first direct in vivo evidence that prolonged administration of MTEP (5 mg/kg) over 7 days leads to the development of tolerance to its antinociceptive effects. Such tolerance was not observed when EMQMCM (5 mg/kg) was administered in the same manner. In conclusion, these results provide additional arguments for the role of group I mGlu receptors in pain with inflammatory conditions.

Analgesics↗

PubMed2006

The role of group I metabotropic glutamate receptors in schizophrenia.

It has been proposed that glutamatergic transmission, in particular NMDA receptor function, might be altered in schizophrenia. This hypothesis is mainly based on the observation that uncompetitive NMDA receptor antagonists, e.g. phencyclidine, evoke psychotic symptoms in healthy subjects, whereas agonists interacting at the glycine site of the NMDA receptor complex, e.g. glycine or D-serine, administered jointly with typical neuroleptics, can alleviate schizophrenic symptoms. The function of NMDA receptors may be modulated by group I mGluRs (mGluR1 and mGluR5), which have also been shown to be altered in schizophrenia. In rodents, mGluR5 antagonists, but not mGluR1 ones, potentiate the locomotor activity and the deficit of prepulse inhibition (PPI) induced by uncompetitive NMDA receptor antagonists. These antagonists (of either type) administered alone are not active in the above tests. Hence, antagonists of mGluR1 and mGluR5 may evoke different effects on the NMDA receptor antagonists-induced behavior and, possibly, on schizophrenic symptoms.

Animals↗

PubMed2006

Antidepressant-like effects of mGluR1 and mGluR5 antagonists in the rat forced swim and the mouse tail suspension tests.

Drugs that act to reduce glutamatergic neurotransmission such as NMDA receptor antagonists exert antidepressant-like effects in a variety of experimental paradigms, but their therapeutic application is limited by undesired side effects. In contrast, agents that reduce glutamatergic tone by blocking type I metabotropic glutamate receptors have been suggested to have more a favorable side-effect profile. The present study aimed to compare the effects of mGluR1 antagonist (EMQMCM; JNJ16567083, 3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate, 0.156-10 mg/kg) and mGluR5 antagonist (MTEP, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine, 1.25-10 mg/kg) in two behavioral screening assays commonly used to assess antidepressant-like activity. In the modified forced swim test in rats, imipramine (used as a positive control) decreased immobility (MED 40 mg/kg) and increased the duration of escape-oriented (climbing and diving; MED 20 mg/kg) behaviors. Both EMQMCM and MTEP decreased the floating duration (MED 1.25 and 2.5 mg/kg) and increased the duration of mobile behaviors (paddling and swimming; MED 2.5 and 5 mg/kg). EMQMCM but not MTEP increased the duration of escape behaviors (climbing and diving; MED 1.25 mg/kg). In the mouse tail suspension test, EMQMCM (5 but not 2.5, 10 and 25 mg/kg), 2-methyl-6-(phenylethynyl)-pyridine (MPEP, 10 but not 1 mg/kg) and MTEP (MED 25 mg/kg) decreased immobility scores. For EMQMCM, the dose-effect relationship was biphasic. With the exception of EMQMCM (10 mg/kg), locomotor activity in mice was not affected by treatments. The present study therefore suggests that acute blockade of mGluR5 and also of mGluR1 exerts antidepressant-like effects in behavioral despair tests in rats and mice.

Animals↗

PubMed2006

Functional interaction of NMDA and group I metabotropic glutamate receptors in negatively reinforced learning in rats.

RATIONALE: The role of glutamatergic system in learning and memory has been extensively studied, and especially N-methyl-D: -aspartate (NMDA) receptors have been implicated in different learning and memory processes. Less is known, however, about group I metabotropic glutamate (mGlu) receptors in this field. Recent studies indicated that the coactivation of both NMDA and group I mGlu receptors is required for the induction of long-term potentiation (LTP) and learning. OBJECTIVE: The purpose of the study is to evaluate if there is a functional interaction between NMDA and group I mGlu receptors in two different models of aversive learning. METHODS: Effects of NMDA, mGlu1, and mGlu5 receptor antagonists on acquisition were tested after systemic coadministration of selected ineffective doses in passive avoidance (PA) and fear-potentiated startle (FPS). RESULTS: Interaction in aversive learning was investigated using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGlu1, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGlu5, and (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate [(+)MK-801] for NMDA receptors. In PA, the coapplication of MTEP at a dose of 5 mg/kg and (+)MK-801 at a dose of 0.1 mg/kg 30 min before training impaired the acquisition tested 24 h later. Similarly, EMQMCM (2.5 mg/kg) plus (+)MK-801 (0.1 mg/kg), given during the acquisition phase, blocked the acquisition of the PA response. In contrast, neither the combination of MTEP (1.25 mg/kg) nor EMQMCM (5 mg/kg) plus (+)MK-801 (0.05 mg/kg) was effective on the acquisition assessed in the FPS paradigm. CONCLUSION: The findings suggest differences in the interaction of the NMDA and mGlu group I receptor types in aversive instrumental conditioning vs conditioning to a discrete light cue.

Animals↗

PubMed2005

Effect of 5-HT3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice.

Phencyclidine and ketamine (but not other NMDA channel blockers, such as memantine) produce psychotomimetic effects. Since unlike memantine, phencyclidine-like compounds show no significant affinity at 5-HT(3) receptors, we investigated if behavioral effects of ketamine could be reduced by 5HT(3) receptor blockade. Ketamine (3-40 mg/kg) produced ataxia, stereotypes and diminished exploratory activity in mice, and reduced prepulse inhibition of acoustic startle response, lowered accuracy in fixed consecutive number and in delayed non-matching-to-sample tasks in rats. The 5HT(3) receptor antagonist MDL 72222 (0.3-3 mg/kg) administration did not reverse any of these deficits and exerted no effects on discriminative stimulus properties of ketamine. In the tail suspension test, both ketamine and MDL 72222 produced anti-immobility effects when given alone (50-66 and 3 mg/kg, respectively) and together (12.5-25 and 1 mg/kg). The present data suggest that 5-HT(3) receptor blockade does not reverse the behavioral deficits of ketamine and may even enhance its certain effects, such as the antidepressant-like action.

Animals↗

PubMed2005

mGluR5, but not mGluR1, antagonist modifies MK-801-induced locomotor activity and deficit of prepulse inhibition.

Hypoglutamatergic theory of schizophrenia is substantiated by observation that high affinity uncompetitive antagonists of NMDA receptors such as PCP can induce psychotic symptoms in humans. Recently, metabotropic glutamate receptors of the mGluR5 type have also been discussed as possible players in this disease. However, less is known about the potential contribution of mGluR1 in schizophrenia. Therefore, the aim of the present study was to compare the effect of selective mGluR1 antagonist EMQMCM, (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and mGluR5 antagonist (MTEP ([(2-methyl-1, 3-thiazol-4-yl) ethynyl] pyridine) either alone or in combination with (+)MK-801 in a prepulse inhibition (PPI) model and locomotor activity tests. Additionally, the effect of both mGluR1 and mGluR5 antagonists on (+)MK-801-evoked ataxia was tested. In contrast to (+)MK-801, which induced disruption of PPI, neither MTEP (1.25-5 mg/kg) nor EMQMCM (0.5-4 mg/kg) altered the PPI. However, MTEP, but not EMQMCM, enhanced disruption of PPI induced by (+)MK-801. Although neither mGluR1 nor mGluR5 antagonists given alone changed locomotor activity of rats, MTEP at 5 mg/kg potentiated the effect of (+)MK-801 while EMQMCM (up to 4 mg/kg) turned out to be ineffective. On the other hand, EMQMCM, but not MTEP, enhanced ataxia evoked by MK-801. The present results demonstrate that blockade of mGluR1 and mGluR5 evokes different effects on behavior induced by NMDA receptor antagonists.

Acoustic Stimulation↗

PubMed2005

Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats.

RATIONALE: Antagonists acting at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists. OBJECTIVE: The present study aimed to evaluate the discriminative-stimulus effects of the NMDA receptor channel blockers (+)MK-801, dextromethorphan, and memantine in rats trained to discriminate nicotine from its vehicle. METHODS: Adult male Wistar rats were trained to discriminate 0.6 mg/kg nicotine from saline under a two-lever, fixed-ratio 10 schedule of food reinforcement. During test sessions, injections of (+)MK-801 (0.03--0.3 mg/kg, i.p.), dextromethorphan (30 mg/kg, s.c.), or memantine (1--10 mg/kg, i.p.) were co-administered with s.c. nicotine (0.075--0.6 mg/kg; interaction tests) or saline (generalization tests). Additional interaction and generalization tests were conducted with the selective nicotinic receptor antagonists mecamylamine (0.1--3 mg/kg, s.c.) and MRZ 2/621 (0.3--10 mg/kg, i.p.), and the mGlu5 receptor antagonist MPEP (3--10 mg/kg, i.p.). RESULTS: In generalization tests, none of the compounds produced any appreciable levels of substitution for nicotine. The nicotine discriminative-stimulus control was dose dependently attenuated by mecamylamine (ED(50)=0.67 mg/kg) and MRZ 2/621 (ED(50)=9.7 mg/kg). Both agents produced a marked downward shift in the nicotine dose-response curve. Memantine and MPEP slightly attenuated nicotine discriminative-stimulus effects, while (+)MK-801 and dextromethorphan did not affect the nicotine-appropriate responding. CONCLUSIONS: NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.

Animals↗

PubMed2005

Excitatory amino acid neurotransmission.

In recent years great progress has been made in understanding the function of ionotropic and metabotropic glutamate receptors; their pharmacology and potential therapeutic applications. It should be stressed that there are already N-methyl-D-aspartate (NMDA) antagonists in clinical use, such as memantine, which proves the feasibility of their therapeutic potential. It seems unlikely that competitive NMDA receptor antagonists and high-affinity channel blockers will find therapeutic use due to limiting side-effects, whereas agents acting at the glycineB site, NMDA receptor subtype-selective agents and moderate-affinity channel blockers are far more promising. This is supported by the fact that there are several glycineB antagonists, NMDA moderate-affinity channel blockers and NR2B-selective agents under development. Positive and negative modulators of AMPA receptors such as the AMPAkines and 2,3-benzodiazepines also show more promise than e.g. competitive antagonists. Great progress has also been made in the field of metabotropic glutamate receptors since the discovery of novel, allosteric modulatory sites for these receptors. Selective agents acting at these transmembrane sites have been developed that are more drug-like and have a much better access to the central nervous system than their competitive counterparts. The chapter will critically review preclinical and scarce clinical experience in the development of new ionotropic and metabotropic glutamate receptor modulators according to the following scheme: rational, preclinical findings in animal models and finally clinical experience, where available.

Animals↗

PubMed2005

NMDA receptor antagonism does not inhibit induction of ischemic tolerance in gerbil brain in vivo.

Effects of high and moderate affinity uncompetitive NMDA receptor antagonists (+)MK-801 and memantine on ischemic tolerance were compared in relation to telemetrically controlled brain temperature. The tolerance to an injurious 3 min test of global forebrain ischemia in Mongolian gerbils was induced 48 h earlier by 2 min preconditioning ischemia. Normothermic preconditioning was virtually harmless, and greatly reduced neurodegeneration evoked by test ischemia. In hyperthermic animals it was injurious and failed to induce tolerance. Memantine (5 mg/kg) and (+)MK-801 (3 mg/kg) injected i.p. 1 h before preconditioning did not inhibit ischemic tolerance in the normothermic gerbils, while in hyperthermic animals treated with (+)MK-801 ischemic tolerance was partially restored. Subchronic 3 day infusion of memantine (30 mg/kg/day) significantly decreased neurodegeneration, and preconditioning in the normothermic gerbils further reduced neuronal damage. Hyperthermia exacerbated preconditioning ischemia and in this way reduced expression of tolerance, while (+)MK-801 partially reversed this effect. Our results do not confirm previous reports on the role of NMDA receptors in the induction of ischemic tolerance in gerbils.

Animals↗

PubMed2005

Effects of mGlu1 and mGlu5 receptor antagonists on negatively reinforced learning.

Effects on aversive learning of the novel highly selective mGlu5 receptor antagonist [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) and mGlu1 receptor antagonist (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) were tested, after systemic administration, in the passive avoidance (PA) and fear potentiated startle (FPS) paradigms. Both MTEP at 10 mg/kg and EMQMCM at 5 and 10 mg/kg, given 30 min before training, impaired acquisition of the passive avoidance response (PAR). Co-administration of MTEP and EMQMCM at doses ineffective when administered alone, produced anterograde amnesia when given 30 min before the acquisition phase. Neither EMQMCM (5 mg/kg) nor MTEP (10 mg/kg) impaired retention of the PAR after direct post-training injections. EMQMCM (5 mg/kg), but not MTEP (10 mg/kg) blocked the PAR when given 30 min before testing. Pre-training administration of MTEP at doses of 2.5 and 5 mg/kg inhibited fear conditioning in the FPS when tested 24 h later. In contrast, EMQMCM was ineffective. Our findings suggest diverse involvement of mGlu1 and mGlu5 receptors in negatively reinforced learning.

Amnesia, Anterograde↗

PubMed2004

Effects of NMDA receptor channel blockers, MK-801 and memantine, on locomotor activity and tolerance to delay of reward in Wistar-Kyoto and spontaneously hypertensive rats.

N-Methyl-D-aspartate (NMDA) receptor blockade enhances motor activity and stimulates dopamine metabolism, effects shared with classical psychostimulant drugs. The present study aimed to characterize behavioral effects of two NMDA receptor channel blockers, MK-801 and memantine, in both Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. In Experiment 1, SHR rats demonstrated higher spontaneous locomotor activity and spent more time in the central area of the open field apparatus compared with WKY rats. Rats of both strains pre-treated with MK-801 (0.01-0.3 mg/kg) or memantine (1-32 mg/kg) demonstrated dose-dependent increases in the total distance traveled and time spent in the central area. Experiment 2 was based on the two-lever discrete-trial delayed reinforcement task in which rats could press one lever to obtain one pellet immediately or another lever for four pellets delivered after a variable delay (0-60 s). Tolerance to delay of reward did not differ between strains. MK-801 (0.03-0.3 mg/kg) and memantine (1-10 mg/kg) produced small, but significant, facilitation of the large-reward lever responding and markedly impaired operant performance at higher dose levels (increased number of missed trials). For both experiments, effects of MK-801 and memantine were more pronounced in WKY compared with SHR rats. Additional studies are needed to address the utility of noncompetitive NMDA receptor blockers in the treatment of attention deficit and hyperactivity disorder.

Animals↗

PubMed2004

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.

Acamprosate↗

PubMed2004

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.

Animals↗

PubMed2003

No nerve growth factor response to treatment with memantine in adult rats.

Nerve growth factor (NGF) is the most widely examined neurotrophin in the experimental models of Alzheimer's disease (AD) and has been shown to prevent the retrograde degeneration of cholinergic neurons. In this study we examined NGF and cholineacetyltransferase (ChAT) changes in several rat brain regions after excitotoxic lesion of the entorhinal cortex with quinolinic acid and tested the effect of memantine on spatial learning in the radial maze after lesion. We observed a significant increase (+26%, p=0.02) of NGF concentrations in the hippocampus of the lesioned rats when compared to sham-lesioned rats. Chronic treatment with memantine showed no significant effect on the NGF increase in the hippocampus (p=0.72). The ChAT activity was significantly increased in the lesioned rats when compared to controls (+16%, p<0.05) and did not depend on treatment with memantine. In spite of this, memantine improved performance of the radial maze. This indicates that memory improving effects of memantine observed in experimental animals and in clinical studies are probably not related to changes in brain NGF content, whereas the observed NGF increase in the denervated hippocampus is probably trauma-related reflecting impaired retrograde transport of hippocampal NGF.

Animals↗

PubMed2002

Amino-alkyl-cyclohexanes as a novel class of uncompetitive NMDA receptor antagonists.

Because of its widespread involvement in the physiology and pathology of the CNS, the glutamatergic system has gained considerable attention as a potential target for development of new agents for a number of therapeutic indications. In this respect, the glutamate receptor subtype of the NMDA type has been most intensively studied. The present review describes the rational for developing amino-alkyl-cyclohexanes, as new uncompetitive NMDA receptor antagonists based on our positive experience with memantine which has been used clinically for many years for the treatment of neurodegenerative dementia. Many amino-alkyl-cyclohexane derivatives have been evaluated in vitro and in animal models, and in turn, one structure, namely neramexane HCl (MRZ 2/579) was selected for further development. This agent shows some similarity to memantine e.g. channel blocking kinetics, voltage dependency, and affinity. Preclinical tests indicated particularly good activity in animal models of alcoholism (self-administration, withdrawal-induced audiogenic seizures etc.) and pain (chronic pain, inhibition of tolerance to the analgesic effects of morphine). It turn, this agent has recently entered phase II of clinical trials in alcoholism after a favourable profile seen in phase I studies.

Animals↗

PubMed2001

Uncompetitive NMDA receptor antagonists potentiate morphine antinociception recorded from the tail but not from the hind paw in rats.

We investigated the effects of pretreatment with low-affinity, uncompetitive NMDA receptor antagonists on morphine-induced antinociception in rats using the same intensity of thermal stimulus applied to the tail and the paws. Similar baseline responses to thermal stimuli of the same intensity were recorded from tails and hind paws. However, morphine produced equal antinociception from the tail and hind paw when used at doses of 2.5 and 6 mg/kg, respectively. These doses were used in further experiments. Thirty minutes before morphine, rats were administered the NMDA receptor antagonists dextromethorphan (2.5--30 mg/kg), memantine (2.5--15 mg/kg) and MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) (1.25--10 mg/kg). All three compounds significantly and dose-dependently potentiated morphine-induced antinociception recorded from the tail. However, none of these NMDA receptor antagonists affected morphine antinociception recorded from the paw. These findings suggest that low-affinity NMDA receptor antagonists modulate differently morphine antinociceptive activity recorded from the tail and hind paws.

Analgesics↗

PubMed2001

Effects of a novel uncompetitive NMDA receptor antagonist, MRZ 2/579 on ethanol self-administration and ethanol withdrawal seizures in the rat.

It has been repeatedly reported that NMDA receptors may contribute to ethanol-induced discriminative stimulus effects and withdrawal syndrome. However, the role of NMDA receptors in the reinforcing properties of ethanol remains unclear. The aim of the present study was to evaluate effects of the novel low-affinity, uncompetitive NMDA receptor antagonist, 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride (MRZ 2/579), on ethanol self-administration and ethanol withdrawal-associated seizures in rats. Both an operant (lever pressing for ethanol) and non-operant two-bottle choice setups were employed to initiate ethanol self-administration. In another procedure, forced treatment with high doses (9--15 g/kg/day) was used to induce physical dependence on ethanol. MRZ 2/579 delivered chronically by osmotic minipumps (9.6 mg/day, s.c.) did not alter either operant or non-operant ethanol drinking behaviour in a maintenance phase of ethanol self-administration. In contrast, repeated daily injections of the drug (5 mg/kg, i.p.) led to a progressive decrease in operant responding for ethanol. MRZ 2/579 (0.5--7.5 mg/kg, i.p.) and another low-affinity NMDA receptor antagonist, memantine (1--10 mg/kg, i.p.) dose-dependently suppressed ethanol withdrawal seizures with efficacies comparable with that of a standard benzodiazepine derivative, diazepam. The results of the present study indicate that: (i) intermittent administration of MRZ 2/579 may lead to a gradual decrease of operant responding for ethanol; and (ii) the group of low-affinity uncompetitive NMDA receptor antagonists may be an interesting alternative to benzodiazepines in the treatment of alcohol withdrawal.

Alcohol Drinking↗