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PubMed2003

Distinct effects of amantadine and memantine on dopaminergic transmission in the rat striatum.

Striatal glutamatergic inputs are known to participate in the modulation of dopaminergic transmission. Accordingly, the non-competitive N-methyl-D-aspartate receptor antagonists memantine and amantadine increase striatal dopamine levels, the latter being widely used in Parkinson's disease therapy. Based on our previous work revealing increased function of dopamine receptors and dopamine transporter after amantadine treatment, we studied the effects of repeated memantine administration on dopaminergic neurotransmission. On rat striatal membranes, dopamine-stimulated [(35)S]GTPgammaS binding was significantly reduced (20%) after 2 days injection with memantine (20 mg/kg per day, i.p.) but not after longer treatments (4 or 7 days). Evaluation of [(3)H]SCH 23390 and [(3)H]spiperone specific bindings only revealed a significant increase in D1 receptor density after 4 or 7 days treatment. Finally, none of these treatments were found to change the activity of the neuronal dopamine transporter in striatal synaptosomes. This shows that amantadine and memantine differentially affect striatal dopaminergic transmission, which could indicate that these two related aminoadamantanes display distinct pharmacodynamic properties.

Amantadine↗
PubMed1997

The NMDA antagonist memantine impairs classical eyeblink conditioning in humans.

The present study investigated the effects of a single oral dose (30 mg) of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist memantine on memory and learning in human subjects. Sixteen male healthy volunteers participated in a double blind placebo controlled study. There were no significant effects of memantine on mood, attention or immediate and delayed verbal and visuospatial memory. Memantine did, however, delay the acquisition of classical eyeblink conditioning and reduced the overall frequency of conditioned responses without affecting reflex or spontaneous eyeblinks. These findings are compatible with the higher affinity of memantine to cerebellar as compared to forebrain tissue and demonstrate the dissociability of different memory systems by pharmacological tools.

Adult↗
PubMed2001

Comparison of the effects of MK-801, ketamine and memantine on responses of spinal dorsal horn neurones in a rat model of mononeuropathy.

Selective ligation of the L5/L6 spinal nerves produces a partial denervation of the hindpaw and has proved to be a useful model for studying the mechanisms underlying neuropathic pain. Two weeks after surgery, in vivo electrophysiological studies were performed in sham operated and nerve injured rats and the responses of spinal dorsal horn neurones to controlled electrical and natural (mechanical and heat) stimuli were recorded. The systemic effects of three N-methyl-D-aspartate receptor (NMDA) antagonists, ketamine (1-10 mg/kg), memantine (1-20 mg/kg) and MK-801 (0.1-5 mg/kg) were compared. Ketamine a clinically available NMDA receptor antagonist, produced greater reductions of the postdischarge, thermal (10 mg/kg, P=0.02), and mechanical evoked responses in spinal nerve ligated (SNL) rats (von Frey 9 g, 1 mg/kg, P=0.04; 5 mg/kg, P=0.01; 10 mg/kg, P=0.05; von Frey 50 g, 5 mg/kg, P=0.02; 10 mg/kg, P=0.003). The inhibition of wind-up was comparable in both animal groups. Memantine produced powerful inhibitions of wind-up after nerve injury with little effect in sham controls (5 mg/kg, P=0.02). The postdischarge, mechanical and thermal evoked responses were reduced to similar extents by memantine in both experimental groups. The effects of MK-801 were comparable between SNL and sham operated rats for all neuronal measures (wind-up, postdischarge, thermal and noxious mechanical evoked responses). The differential blocking abilities of these antagonists on the various neuronal responses may relate to the characteristics of their voltage-dependent blockage of the channel associated with the receptor. The favourable side effect profile of memantine supports its potential use for the treatment of neuropathic pain.

Animals↗
PubMed2003

Efficacy of the NMDA-receptor antagonist memantine in patients with chronic phantom limb pain--results of a randomized double-blinded, placebo-controlled trial.

Phantom limb pain (PLP) associated neuroplastic changes are partly mediated by excitatory amino acids at NMDA receptor sites. This study was undertaken to deduce if NMDA-receptor antagonists may be effective in patients with chronic PLP. Therefore a four week double-blinded, randomized placebo-controlled trial was performed to evaluate the efficacy of 30 mg memantine/day, an orally administrable NMDA receptor antagonist.Thirty-six patients, 18 per group, with a history of at least 12 months PLP and an average pain of at least 4 on the 11-point numeric rating scale (NRS) were enrolled. The patients completed a standardized questionnaire before the trial. PLP intensity and the level of eight complaints were assessed during the trial. Number needed to treat (NNT) was calculated based on the average PLP during the 3rd week (steady state). In both groups, PLP declined significantly in comparison with the baseline (verum: 5.1 (+/-2.1) to 3,8 (+/-2,3), placebo from 5.1 (+/-2.0) to 3.2 (+/-1,46) NRS) without a re-rising of the PLP during the washout period. Mean pain relief was 47% in the memantine group (10 patients reported more than 50% relief), 40% in the placebo group (6>50%): NNT were 4.5 (KI: 2.1-10.6). Analysis of covariance demonstrated a significant impact only on the prior PLP intensity, but no treatment effect. Two patients have demonstrated long-term pain relief under memantine until now (16 months). The total number of slight adverse events were comparable in both groups, but the overall number of severe events was higher in the memantine group (P<0.05). This trial failed to demonstrate a significant clinical benefit of the NMDA-receptor antagonist memantine in chronic PLP. The administration of a higher dosage is probably not tolerable.

Adult↗
PubMed2006

Reinstatement of morphine-conditioned reward is blocked by memantine.

Protection of abstinent individuals from relapse is the main goal of drug dependence treatment. Relapse is frequently precipitated by exposure to small doses of the drug of abuse or exposure to the environment that was previously associated with the drug. Mice exposed to morphine (10 mg/kg) in a unique test-box environment display a conditioned place preference for this environment. Such preference can be extinguished by subsequent pairing of physiological saline administration with the same environment. Once extinguished, the original place preference can be reinstated after a priming dose (1-2.5 mg/kg) of morphine is given. However, mice treated with 7.5 (but not 3.75) mg/kg of memantine (the glutamate/NMDA receptor antagonist) during the extinction phase were insensitive to morphine's ability to reinstate the place preference 2 days after extinction conditionings. Effect of memantine was also observed when priming dose of morphine was given 21 days after extinction conditionings. In contrast, morphine's ability to reinstate conditioned response was not affected by treatment with 10 mg/kg of chlordiazepoxide, 0.5 mg/kg of LSD-25, or 1 mg/kg of morphine given during extinction conditionings. A separate experiment demonstrated that memantine (7.5 mg/kg) treatment did not affect learning. We show for the first time that memantine treatment during extinction conditionings may abolish the ability of drug-related cues to evoke reinstatement, suggesting that this NMDA receptor antagonist can be useful in preventing relapse in opioid dependent individuals.

Animals↗
PubMed2006

[Memantine and Complex Regional Pain Syndrome (CRPS): effects of treatment and cortical reorganisation].

BACKGROUND: In recent studies a central nervous system involvement in the pathogenesis of Complex Regional Pain Syndrome (CRPS) was suggested, stimulating the introduction of central acting drugs. Animal studies have demonstrated an increased expression of the N-methyl-D-aspartate (NMDA) receptors in experimental neuropathic pain. PURPOSE: The aim of this study was to investigate the relationship between NMDA receptor blockers and CRPS. METHOD: Three patients suffering from CRPS of one upper extremity where treated with oral NMDA antagonist Memantine for eight weeks. Patients expressed their pain levels with a visual analog scale ranging from zero to ten at rest and after fist clenching. Furthermore, the range of movement of the fingers and the wrist were documented. To assess force, a pinchmeter and a dynamometer were used. Cortical reorganisation was studied with functional Magnetic Resonance Imaging (fMRI) and Magnetoencephalography (MEG). RESULTS: Six months after treatment with Memantine no rest pain was present in any of the patients. Furthermore, an increase in finger movement was observed after six-month follow-up with no deficits and free movement ranges. Additionally, wrist movement was improved and an increase of force was measured after six months with the dynamometer and the pinchmeter. Moreover the functional impairment, cortical reorganisation was observed in all patients before treatment. These changes returned to a normal pattern after eight weeks of treatment with Memantine. CONCLUSION: These first results demonstrate central nervous system involvement in the development and maintenance of CRPS. The results (functional, pain, fMRI, MEG) after treatment with Memantine indicate the importance of the NMDA receptor system in neuropathic pain syndromes and provide a promising approach for the treatment of CRPS.

Administration, Oral↗
PubMed2006

A placebo-controlled study of memantine for the treatment of human immunodeficiency virus-associated sensory neuropathy.

Distal sensory polyneuropathy (DSP) is the most frequent neurological complication of HIV infection. Neuropathic symptoms vary from mild paresthesias to severe pain that respond only partially to symptomatic treatment. Forty-five subjects with human immunodeficiency virus (HIV)-associated symptomatic DSP (SDSP) were enrolled in a randomized, multicenter, 16-week placebo-controlled study of memantine, an N-methyl-D-aspartate (NMDA) uncompetitive antagonist. Although memantine was well tolerated, no trend toward clinical benefit was observed. Results were similar to those of other pilot studies of memantine for neuropathic pain unrelated to HIV, suggesting that memantine is ineffective for the symptomatic treatment of HIV-associated SDSP.

Adult↗
PubMed1994

Memantine inhibits [3H]MK-801 binding to human hippocampal NMDA receptors.

The antispastic agent and N-methyl-D-aspartate (NMDA) receptor antagonist memantine has recently been proposed as a neuroprotective drug for use in patients with dementia syndromes with primarily temporal lobe pathology, e.g. senile dementia of Alzheimer type or dementia in Parkinson's disease. In a quantitative autoradiographic study in human post mortem hippocampus, memantine was able to inhibit binding of the noncompetitive NMDA-antagonist [3H]MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate) with inhibition constants between 3 and 10 microM, being about a factor of 10 more potent than the dissociative anaesthetic and NMDA receptor antagonist (+/-)ketamine. As these inhibition constants are well within the therapeutic concentration range of memantine, antagonism of endogenous glutamate at limbic NMDA receptors may be one molecular mechanism by which memantine is beneficial in dementia syndromes.

Aged↗
PubMed1998

The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans.

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.

Adult↗
PubMed2002

Memantine does not block antiaggressive effects of morphine in mice.

The action of the noncompetitive N-methyl-D-aspartate (NMDA) receptor blocker memantine (5, 10, 20 and 40 mg/kg) was evaluated during social encounters in mice. Although a dose-dependent increase in locomotion was observed, only with the highest dose did it reach statistical significance. Aggressive behavior was decreased with 20 and 40 mg/kg of memantine, social contacts being increased only with 20 mg/kg. Subsequently, the effect of these memantine doses on the antiaggressive actions of morphine (10 mg/kg) was evaluated. None of the doses affected the antiaggressive action of morphine. As memantine administration produced an antiaggressive effect only at doses that affected locomotion, it is unlikely that the glutamatergic system mediates the antiaggressive actions of morphine.

Adaptation, Psychological↗
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↗
PubMed2003

Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy.

Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective in dementia, including Alzheimer disease (AD). Therefore, its combination with acetylcholinesterase inhibitors (AChEIs) is anticipated. We report a postmarketing surveillance study conducted among German physicians who, during routine clinical practice, treated demented patients with memantine in combination with an AChEI. Most of the 158 surveyed patients (mean age, 74 years) were diagnosed with AD but other dementias were included. Memantine was prescribed at a wide range of daily doses (median, 20 mg/day) and was combined with donepezil for most patients (84%). Combination therapy was well tolerated for nearly all patients (98%) for an average observation period of 4 months at stable doses of both antidementia agents. No serious adverse drug reaction (ADR) was reported. No ADR or change in blood chemistry was experienced by most patients (96% and 81%, respectively); the six reported ADRs resolved without sequelae and without drug discontinuation. Global clinical status of most patients was judged as improved (54%) or stable (39%) over the observation period. These findings particularly suggest that memantine in combination with AChEIs is safe and well tolerated.

Adult↗
PubMed2006

Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer's disease who failed to benefit from previous cholinesterase inhibitor treatment.

We investigated the efficacy and safety of rivastigmine alone and combined with memantine in Alzheimer's disease patients previously failing on donepezil or galantamine. This was a prospective, open-label, multicentre study. After stopping donepezil or galantamine, patients received rivastigmine 3-12 mg/day for 16 weeks. Non-responders to rivastigmine monotherapy at week 16 received memantine 5-20 mg/day plus rivastigmine for 12 weeks. The primary efficacy parameter was response (Mini-Mental State Examination equal or better than at week 16) to dual therapy at week 28. Secondary criteria were changes on cognitive and behavioural scales. Two hundred and two patients were included. Ninety-three (46.3%) patients responded to rivastigmine monotherapy. Of 86 patients receiving additional memantine for another 12 weeks, 67 (77.9%) responded. Combination therapy caused no apparent safety concerns. When patients fail on donepezil or galantamine, switching to rivastigmine may improve cognition and behaviour. Should they continue to deteriorate, the addition of memantine may be beneficial.

Aged↗
PubMed1996

Comparative patch-clamp studies with freshly dissociated rat hippocampal and striatal neurons on the NMDA receptor antagonistic effects of amantadine and memantine.

Patch- and concentration-clamp techniques were used to compare the effects of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists (+)-MK-801 (dizocilpine, (+)-5-methyl-10, 11-dihydro-5H-dibenzocyclohepten-5, 10-imine maleate), ketamine, memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) on agonist-induced inward currents in freshly dissociated rat hippocampal and striatal neurons. In hippocampal neurons, ketamine (5 microM), menantine (10 microM) and amantadine (100 microM) selectively antagonized inward current responses to NMDA (500 microM plus glycine 5 microM) in a voltage-dependent manner without affecting responses to (s)-alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (100 microM) or gamma-aminobutyric acid (10 microM). The NMDA receptor antagonistic effect of all four agents was typical of open channel blockade. The kinetics of blockade/unblockade was inversely related to antagonist affinity. In hippocampal neurons amantadine was the least potent NMDA receptor antagonist (IC50 18.6 +/- 0.9 microM) and showed the fastest blocking kinetics, whereas (+)-MK-801 was the most potent (IC50 0.12 +/- 0.01 microM) and showed the slowest blocking kinetics. Memantine (IC50 1.04 +/- 0.26 microM) and ketamine (IC50 0.43 +/- 0.10 microM) were almost equipotent and had similar, intermediate blocking kinetics. In striatal neurons recorded under identical conditions (+)-MK-801, ketamine and memantine were 3- to 4-fold less potent whereas amantadine was somewhat more potent than on hippocampal neurons. This could offer an explanation for the better clinical profile of amantadine in Parkinson's disease, as therapeutically relevant concentrations of amantadine are likely to be more active in the striatum whereas memantine is likely to be more active in other structures.

Amantadine↗
PubMed2005

Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice.

An increasing number of studies suggest that the present clinical therapy used in Alzheimer's disease (AD), in addition to having a symptomatic effect, also may interact with the ongoing neuropathological processes in the brain. The aim of this study was to investigate the effect of the cholinesterase inhibitor galantamine and the N-methyl-d-aspartate (NMDA) antagonist memantine in comparison to nicotine on the neuropathology of Tg2576 transgenic mice (APPswe). Nontransgenic and APPswe mice at 10 months of age were treated subcutaneously with saline, memantine, galantamine, or nicotine for 10 days. Nicotine reduced the guanidinium-soluble amyloid-beta peptide (Abeta) levels by 46 to 66%, whereas the intracellular Abeta levels remained unchanged. Treatment with nicotine also resulted in less glial fibrillary acidic protein immunoreactive astrocytes around the plaques, increased levels of synaptophysin, and increased number of alpha7 nicotinic acetylcholine receptors (nAChRs) in the cortex of APPswe transgenic mice. Galantamine treatment caused an increase in the cortical levels of synaptophysin in the APPswe mice. Memantine treatment reduced the total cortical levels of membrane-bound amyloid precursor protein (45-55%) in both transgenic and nontransgenic mice, which eventually may decrease the level of Abeta. In conclusion, galantamine, memantine, and nicotine have different interactions with Abeta processes, alpha7 nAChRs, and NMDA receptors in APPswe mice. These different effects might have therapeutic relevance, and this knowledge might be applicable to the development of new effective therapeutic strategies for AD.

Amyloid beta-Peptides↗
PubMed2006

The effects of gabapentin and memantine in acquired and congenital nystagmus: a retrospective study.

BACKGROUND: Pharmacological treatment has been successful in some forms of acquired neurological nystagmus. However, drugs are not known to be effective in idiopathic infantile nystagmus or nystagmus associated with ocular diseases. METHODS: The authors retrospectively analysed Snellen visual acuity (VA), subjective visual function, and eye movement recordings of 23 patients with nystagmus (13 secondary to multiple sclerosis, three associated with other neurological diseases, two idiopathic infantile, and five with associated ocular diseases) treated with gabapentin or memantine. RESULTS: With gabapentin, 10 of 13 patients with nystagmus secondary to multiple sclerosis (MS) showed some improvement. Memantine improved the VA in all three patients with MS who did not improve on gabapentin. There was no change of nystagmus in other neurological disorders. Patients with congenital nystagmus showed reduction of nystagmus and their VA changes depended on the ocular pathology. CONCLUSION: Gabapentin and memantine may be effective in acquired nystagmus secondary to MS. To the authors' knowledge this is the first series of patients showing that gabapentin is effective in improving nystagmus in congenital nystagmus/nystagmus associated with ocular pathology. Memantine may be useful as an alternative drug in treating patients with nystagmus.

Adolescent↗
PubMedDate not supplied

Memantine suppresses the glutamatergic neurotransmission of mammalian inner hair cells.

The glutamatergic synapses between inner hair cells and afferent neurons seem to be involved in pathophysiological conditions of the cochlea. The excessive release of glutamate from inner hair cells during noise trauma and ischemia affects the afferent neurons. It is possible that in tinnitus outer hair cell or inner hair cell dysfunction or damage leads to an altered spontaneous release of glutamate from inner hair cells. Thus, the pharmacological modulation of glutamatergic neurotransmission could be of great value in the therapy of certain inner ear diseases. Recently, it has been discovered that the spasmolytic drug memantine has antiglutamatergic properties. As a possible drug for inner ear diseases, we were interested in the action of memantine on the neurotransmission of inner hair cells. With the aid of microiontophoretic techniques we were able to show a strong depressing effect on spontaneous activity as well as on glutamate-induced activity. This effect seems to be mediated by a blockade of N-methyl-D-aspartate (NMDA) receptors as memantine showed a strong inhibiting effect on NMDA-induced activity but not on AMPA-induced activity. These results recommend memantine for the treatment of inner ear diseases, e.g. especially tinnitus.

Animals↗
PubMed2004

Specific functional effects of memantine treatment in patients with moderate to severe Alzheimer's disease.

Treatment of Alzheimer's disease (AD) that combats progressive functional deterioration can improve the patient's quality of life and reduce caregiver burden. Memantine, a moderate affinity N-methyl-D-aspartate receptor antagonist, reduces global deterioration in AD patients and provides cognitive and functional benefits relative to placebo. Two previous studies reported statistically significant benefits of memantine for overall functional ability on the Alzheimer Disease Cooperative Study Activities of Daily Living Inventory modified for severe dementia (ADCS-ADL(19)), Functional Assessment Staging, and G2 scale. The present study reports a single-item analysis of the ADL scales from the two trials and shows that patients treated with memantine demonstrated a numerical advantage over placebo on all items assessed. These results help to translate the positive effects of memantine into specific aspects of functional ability, information that is relevant to AD patients and their families as well as to researchers interested in the assessment of functional ability in AD clinical trials.

Activities of Daily Living↗