Memantine in moderate to severe Alzheimer's disease.
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Memantine plus donepezil improves physical and mental health in people with Alzheimer's disease.
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Drug treatment for Alzheimer's disease. Commentary: Memantine treatment in patients with moderate-to-severe Alzheimer's disease already receiving donepezil: a randomized controlled trial.
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Journal Article↗
A word of caution in extrapolating the spinal cord protective effects of memantine obtained in a rabbit model under ketamine anesthesia
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Memantine was better than placebo in Alzheimer disease already being treated with donepezil.
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[Mémantine (Ebixa): a new therapeutic strategy for the treatment of moderate to severe forms of Alzheimer's disease].
Alzheimer's disease has definitively emerged from its ghetto and has been identified as a (priority) public health concern in view of the increasing age of the population. Considerable advances have been made in this disease over the last 15 Years, with progress in the following fields: knowledge of the underlying aetiopathogenetic, genetic and biochemical mechanisms; semiological, clinical and paraclinical approaches; creation of early diagnostic centres and multidisciplinary care networks; therapy available to patients or currently under development. The four existing acetylcholinesterase inhibitors having confirmed symptomatic action in patients with mild to moderate Alzheimer's disease have now been joined by memantine (Ebixa), a non-competitive agonist of N-methyl-D-aspartate (NMDA) receptors. One pathogenic mechanism of Alzheimer's disease appears to be hyperactivity of the glutaminergic neurons. Various preclinical studies have shown that memantine (Ebixa) inhibits glutaminergic hyperactivity in Alzheimer's disease through modulation of NMDA receptors. Since the early 1990s, several controlled clinical trials in patients with moderate to severe Alzheimer's disease (3<MMSE< or =14) have demonstrated the efficacy of memantine on cognitive criteria (cognitive evaluation of severe dementia) (Severe Impairment Battery--SIB), functional criteria (Functional Assessment Stage--FAST) and global clinical criteria (Clinician's Interview-Based Impression of Change--CIBIC-Plus). The data from these studies together with clinical experience of memantine in Germany since 1982 confirm the safety of use and good tolerability profile of this medication at the recommended dosages (10 to 30 mg/day). Treatment with memantine reduces the global costs of the disease by lightening the burden on helpers and delaying institutionalisation of patients. These different studies have resulted in approval of memantine in this particular indication by the European Medicines Agency. The efficacy of memantine in mild to moderate Alzheimer's disease is currently being assessed. The preliminary results also appear to militate in favour of the efficacy of the drug in certain forms of vascular dementia. Finally, the good safety profile of combined use of this drug with antiacetylcholinesterases opens up a realistic perspective of bitherapy in Alzheimer's disease.
Aged↗
Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo.
The amino-adamantane derivatives memantine (1-amino-3,5-dimethyladamantane) and amantadine (1-amino-adamantane) are relatively low affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease respectively for several years without serious side effects. The aim of this study was to test whether memantine, amantadine and other low affinity uncompetitive NMDA receptor antagonists also have better therapeutic indices than high affinity antagonists in preclinical models of epilepsy by assessing the potency, kinetics and voltage-dependency of open channel blockade for a series antagonists in vitro and comparing these effects to anticonvulsive and motor impairment activity in vivo. The compounds tested were memantine, amantadine, 14 other amino-adamantanes, (+)-MK-801, ketamine, dextrorphan, dextromethorphan and phencyclidine. The offset kinetics of open-channel blockade assessed with whole cell patch clamp recordings from cultured superior colliculus neurones were highly correlated to potency i.e. the less potent antagonists showed faster unblocking kinetics (Koff, r = 0.904). Although, onset kinetics as assessed by Kon were not correlated to potency (r = 0.023), tau on estimated at IC50 is perhaps a more meaningful measure of onset kinetics at equieffective concentrations and was also well correlated to potency (r = -0.863). All amino-adamantanes tested were strongly voltage-dependent. There was also a good correlation between the in vitro potencies of uncompetitive NMDA receptor antagonists assessed with patch clamp recordings and displacement of equilibrium [3H](+)-MK-801 binding and their in vivo activity against maximal electroshock (MES) and pentylenetetrazol (PTZ) induced tonic convulsions and NMDA-induced lethality in mice. Memantine and four other amino-adamantanes with somewhat lower potency and faster blocking kinetics had better therapeutic indices (ED50 rotarod and traction reflex over ED50 in MES-induced convulsions; TI = 2-4) than substances with higher affinity such as ketamine, dextrorphan and (+)-MK-801 (TI < 2). However, amantadine and several other amino-adamantanes with lower potency than memantine actually had poorer therapeutic indices (TI < or = 0.5) which may have been due to additional actions at other ion channels or receptors at the doses necessary to protect against seizures. In fact, ED50 in the MES test was negatively-correlated to therapeutic indices (traction r = -0.790, rotarod r = -0.797) i.e. the less potent uncompetitive antagonists had worse therapeutic indices. The data from the present study do not lend support to the idea that low affinity, open channel NMDA receptor blockers are also effective in models of epilepsy at doses having little effect on physiological processes. It should be stressed that these data do not contradict the known therapeutic safety of memantine and amantadine in dementia and Parkinson's disease respectively. Thus the good clinical profile of memantine in dementia has been attributed not only to its fast blocking/unblocking kinetics but also to its strong voltage-dependency. These biophysical properties may allow therapeutically-relevant concentrations to block chronic, low level pathological activation of NMDA receptors whilst leaving their synaptic activation intact. Precisely these properties may also underlie the poor therapeutic indices seen in the present study on antiepileptic activity due to the synaptic nature of both seizures and normal glutamatergic transmission.
Amantadine↗
The chemical biology of clinically tolerated NMDA receptor antagonists.
Most neuroprotective drugs have failed in clinical trials because of side-effects, causing normal brain function to become compromised. A case in point concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids, such as glutamate itself, is thought to contribute to neuronal damage in many neurological disorders ranging from acute hypoxic-ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurological diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor-channel complex. These include drugs acting at the agonist (NMDA) or co-agonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side-effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, even although effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block with the property of uncompetitive antagonism is the most appealing strategy for therapeutic intervention during excessive NMDAR activation as this action of blockade requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiological neurotransmission. Utilizing this molecular strategy of action, we review here the logical process that we applied over the past decade to help develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderate-to-severe Alzheimer's disease while being well tolerated. Memantine is also currently in trials for additional neurological disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. Additionally, taking advantage of memantine's preferential binding to open channels and the fact that excessive NMDAR activity can be down-regulated by S-nitrosylation, we have recently developed combinatorial drugs called NitroMemantines. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs in order to avoid systemic side-effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies appear to have even greater neuroprotective properties than memantine.
Apoptosis↗
Anticonvulsant action of 1,3-dimethyl-5-aminoadamantane. Pharmacological studies in rodents and baboon, Papio papio.
The anticonvulsant actions of memantine (1,3-dimethyl-5-aminoadamantane) have been evaluated in mice (seizures induced by maximal electroshock, pentylenetetrazol, bicuculline, picrotoxin, 3-mercaptopropionic acid and N-methyl-D,L-aspartic acid) and in photosensitive baboons, Papio Papio (clonic responses to intermittent photic stimulation). Memantine, 5-20 mg/kg, raised the threshold for electroconvulsions and protected mice against the tonic hind limb extension in pentylenetetrazol-, bicuculline-, picrotoxin- and 3-mercaptopropionic acid-induced seizures, but was ineffective against the clonic phase of chemically-induced seizures. In the baboons, no protection against photomyoclonic responses was observed within 5 h after the intravenous administration of memantine, 1-9 mg/kg. Amantadine, 100 mg/kg, reduced the protective effect of memantine against electroconvulsions. Apomorphine, haloperidol, pimozide, spiroperidol and bicuculline did not modify the anticonvulsant activity of memantine in electroconvulsions. These studies demonstrate an anticonvulsant action of memantine in rodents and suggest that dopaminergic mechanisms do not contribute to its mechanism of action.
Amantadine↗
Motor impairment produced by ethanol and site-selective NMDA receptor antagonists in mice: tolerance and cross-tolerance.
Current perspectives on clinical use of N-methyl-D-aspartate (NMDA) receptor antagonists infer acute and repeated administration schedules for management of different pathological states. Development of tolerance and cross-tolerance between different antagonists may significantly affect their clinical effectiveness. Since ethanol was repeatedly demonstrated to act as NMDA receptor antagonist, ethanol use may also have its impact on the effects of NMDA receptor ligands. Using the rotarod test in mice, the present study evaluated development of tolerance and cross-tolerance between ethanol (3.2 g/kg, p.o.), competitive NMDA receptor antagonist, D-CPPene (5.6 mg/kg, i.p.), and low-affinity NMDA receptor channel blocker, memantine (30 mg/kg, i.p.), that were administered for seven days once a day after the daily rotarod training session. Acute tests with ethanol (0.3, 1, 1.7, 3.2 g/kg), D-CPPene (0.3, 1, 3, 5.6 mg/kg) and memantine (1, 3, 10, 30 mg/kg) revealed that (a) each of these drugs dose-dependently disrupted rotarod performance in drug-naive mice; (b) in ethanol- and D-CPPene-treated mice, tolerance was observed to ethanol and D-CPPene but not to memantine; moreover, effects of memantine were even more pronounced in D-CPPene-treated subjects; and (c) repeated memantine administration decreased acute motor impairing effects of ethanol, D-CPPene and memantine. Thus, the history of ethanol use or abuse may influence pharmacological activity of NMDA receptor antagonists and this effect is dependent on type of the NMDA receptor antagonist applied.
Animals↗
Contemporary issues in the treatment of Alzheimer's disease: tangible benefits of current therapies.
Because of the mild symptomatology associated with its earlier stages, Alzheimer's disease (AD) is most commonly diagnosed in an intermediate to late stage of progression. Patients with moderate to severe AD at diagnosis have already experienced appreciable losses in cognition and functioning. However, such patients may still benefit greatly from the use of antidementia agents such as cholines-terase inhibitors (ChEIs) and the N-methyl-D-aspartate (NMDA) receptor open-channel antagonist memantine. Monotherapy regimens involving a ChEI or memantine have been shown to slow the progression of cognitive symptoms in patients with moderate to severe AD, although memantine is currently the only agent approved for use in this setting. Furthermore, combination therapy involving memantine and a ChEI has been shown to yield increased cognitive benefits relative to ChEI monotherapy, a result that is believed to be attributable to the distinct therapeutic mechanisms associated with NMDA receptor open-channel antagonists and ChEIs. Nonetheless, recent findings indicate that the therapeutic effects of these antidementia agents are not limited to cognition. For example, emerging data highlight the efficacy of ChEIs and memantine, used either alone or in combination, in improving outcomes related to patient functioning and behavior, 2 domains that may have a great deal of significance for patients and caregivers. Furthermore, recent clinical trial data suggest that antidementia agents may significantly delay nursing home placement, a unique endpoint that can be tremendously distressing to patients with AD and their caregivers. Thus, it is clear that the ChEIs and memantine provide substantial benefits that extend across the spectrum of symptoms of AD, improving outcomes for those who are affected, either directly or indirectly, by this debilitating condition.
Alzheimer Disease↗
Antinociceptive activity of the N-methyl-D-aspartate receptor antagonist N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) in experimental models of inflammatory and neuropathic pain.
N-(2-Indanyl)-glycinamide hydrochloride (CHF3381) is a novel low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist. The current study compared the antinociceptive effects of CHF3381 with those of gabapentin and memantine in in vitro and in vivo models of pain. In isolated rat spinal cord, CHF3381 and memantine, but not gabapentin, produced similar inhibition of the wind-up phenomenon. CHF3381 suppressed the maintenance of carrageenan-induced thermal and mechanical hyperalgesia in the rat with a minimum significantly effective dose (MED) of 30 mg/kg p.o. Memantine produced a partial reversal of both thermal and mechanical hyperalgesia (MED = 10 and 15 mg/kg i.p., respectively). Gabapentin reversed mechanical hyperalgesia (MED = 10 mg/kg s.c.), but did not affect thermal hyperalgesia. In the mouse formalin test, CHF3381 and memantine preferentially inhibited the late phase (MED = 30 and 20 mg/kg i.p., respectively); gabapentin inhibited only the late phase (MED = 30 mg/kg s.c.). Unlike morphine, CHF3381 chronic administration was not accompanied by the development of tolerance in the formalin test. Furthermore, morphine tolerance did not cross-generalize to CHF3381. In rats with a sciatic nerve injury, CHF3381 relieved both cold and mechanical allodynia (MED = 100 mg/kg p.o.). In contrast, memantine was inactive. Gabapentin blocked cold allodynia (MED = 30 mg/kg s.c.), but had marginal effects on mechanical allodynia. In diabetic neuropathy, CHF3381 reversed mechanical hyperalgesia (MED = 50 mg/kg p.o.). Memantine (15 mg/kg i.p.) produced an antinociceptive effect, whereas gabapentin (100 mg/kg p.o.) had no significant effect. Thus, CHF3381 may be useful for the therapy of peripheral painful neuropathies.
Animals↗
Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice.
RATIONALE: It has been hypothesized that low-affinity, uncompetitive N-methyl-d-aspartate (NMDA) antagonists may have therapeutic efficacy (e.g., in epilepsy, stroke, drug dependence) without the adverse side effects associated with high-affinity ligands (e.g., dizocilpine, phencyclidine). OBJECTIVES: To determine whether low-affinity NMDA antagonists have a larger predicted therapeutic window than high-affinity ligands. METHODS: In Swiss-Webster mice, we compared the effects of uncompetitive antagonists having a range of affinities for the NMDA receptor ion channel [dizocilpine, memantine, ibogaine, amantadine and 5-aminocarbonyl-10, 11-dihydro-5h-dibenzo[a,d] cyclohepten-5,10-imine (ADCI)] in three behavioral assays typically used to assess NMDA receptor antagonism. Behavioral side effects were compared with the efficacy of the compounds to protect against NMDA-induced seizures. RESULTS: Only dizocilpine and memantine substituted fully in mice trained to discriminate dizocilpine from saline. Dizocilpine (K(i) approximately 0.003 microM) protected against NMDA-induced convulsions at doses that produced ataxia and stimulation of locomotor activity. Conversely, memantine (K(i) approximately 0.54 microM) prevented convulsions at doses that were 8- to 18-fold lower than those producing ataxia or effects on locomotion, respectively. Indeed, in contrast to dizocilpine, memantine did not stimulate locomotor activity but only produced dose-dependent reductions. The low-affinity antagonists ibogaine (K(i) approximately 1 microM) and ADCI (K(i) approximately 11 microM) protected against convulsions at doses that produced significant dizocilpine-like discriminative stimulus effects, ataxia and decreases in locomotor activity. Amantadine (K(i) approximately 11 microM) was ineffective against NMDA-induced convulsions up to doses that produced significant behavioral side effects. CONCLUSIONS: These findings indicate that only certain low-affinity, uncompetitive NMDA antagonists (e.g., memantine) may have therapeutic efficacy at doses that do not produce an adverse side-effect profile. For other therapeutic endpoints, different estimates of efficacy and safety require derivation.
Animals↗
Anti-allodynic interactions between NMDA receptor channel blockers and morphine or clonidine in neuropathic rats.
Previous studies suggested that combining N-methyl-d-aspartate (NMDA) receptor antagonists with either mu-opioid agonist morphine or alpha2-adrenoreceptor agonist clonidine results in the significant synergistic enhancement of analgesic activity in the animal models of acute and neuropathic pain. When given alone, NMDA receptor antagonists, morphine and clonidine are capable of attenuating tactile allodynia associated with chronic nerve injury. The present study aimed to assess anti-allodynic effects of these compounds and to test additivity of these interactions using isobolographic analysis. Adult male Wistar rats with unilateral loose ligation of sciatic nerve developed significant tactile allodynia (between-paw difference of about 18-20 g). In separate groups of animals, dose-dependent anti-allodynic activity was confirmed for memantine (1.8-17.8 mg/kg), neramexane (1.8-17.8 mg/kg), morphine (1-10 mg/kg) and clonidine (0.01-0.1 mg/kg). In a subsequent series of experiments, memantine (or neramexane) and morphine (or clonidine) were co-administered at the fixed equi-effective dose ratios (six dose levels per drug combination). None of the tested combinations produced supra-additive, synergistic effects. In fact, memantine+clonidine, neramexane+clonidine and morphine+neramexane were producing simple additive effects, while morphine+memantine was characterized as the infra-additive combination. Thus, despite expectations based on previous studies, NMDA receptor channel blockers, memantine and neramexane, produce no synergistic interactions with either morphine or clonidine when administered acutely to rats with nerve injury-induced tactile allodynia.
Adrenergic alpha-2 Receptor Agonists↗
Pharmacotherapeutic approaches to the treatment of Alzheimer's disease.
BACKGROUND: Alzheimer's disease (AD), a progressive degenerative disorder of the brain, is the most common cause of cognitive impairment in the elderly. The pharmacotherapy of AD is evolving rapidly. Cholinergic stabilization with cholinesterase-inhibitor (ChEI) therapy implies neuroprotection and a resultant slowing of disability and disease progression. The moderate-affinity N-methyl-d-aspartate (NMDA)-receptor antagonist memantine may block neural excitotoxicity. OBJECTIVE: The purpose of this review was to examine the evidence for the responsiveness to pharmacotherapy of established AD; specifically, the extent to which the benefits of therapy have been proved, the extent to which currently available ChEIs support cholinergic neurotransmission, and the extent to which currently available ChEIs and memantine provide neuroprotection. METHODS: Relevant studies were identified through a comprehensive search of MEDLINE for articles published between January 1999 and February 2004 using the terms Alzheimer's pharmacotherapy, cholinesterase inhibitor therapy, Alzheimer's disease, donepezil, rivastigmine, galantamine, glutamatergic system modifiers, and memantine; a search of the reference lists of identified articles; and a manual search of pertinent journals. Articles were selected that contained higher-level evidence, based on explicit validated criteria. RESULTS: ChEI therapy was associated with quality-of-life improvements that included enhanced performance of activities of daily living, reduced behavioral disturbances, stabilized cognitive impairment, decreased caregiver stress, and delay in the first dementia-related nursing home placement. In large clinical trials in moderate to severe AD (a stage that is associated with distress for patients and caregiver burden, and for which other treatments are not available), memantine showed an ability to delay cognitive and functional deterioration. The combination of memantine and ChEI therapy was significantly more efficacious than ChEI therapy alone (P < 0.001) and was well tolerated. CONCLUSIONS: The idea that AD is pharmacologically unresponsive appears to be changing. With the use of ChEI and NMDA-receptor antagonist therapy, the symptoms and outcomes of this devastating neurodegenerative disease can be improved and its course altered.
Activities of Daily Living↗
Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents--preclinical studies.
Aminoadamantanes such as 1-aminoadamantane (amantadine) and 1-amino-3,5-dimethyladamantane (memantine) are N-methyl-D-aspartate (NMDA) receptor antagonists which show antiparkinsonian-like activity in animal models and in Parkinson's patients. The issue of whether NMDA antagonism plays a role in the symptomatological antiparkinsonian activity of amantadine and memantine is addressed by comparing: behaviourally effective doses, serum/brain levels, and their potency as NMDA receptor antagonists. In the case of memantine, blockade of NMDA receptors is probably the only mechanism responsible for antiparkinsonian activity, whereas for amantadine the situation is clearly far more complex. There are a number of differences between memantine and amantadine both in vitro and in vivo, and although NMDA receptor antagonism certainly participates in the antiparkinsonian activity of amantadine, other effects, some of which are elusive, also play a role. Moreover, it has been suggested that the pathomechanism of Parkinson's disease involves excitotoxic processes and that treatment with NMDA receptor antagonists might also slow the progression of neurodegeneration. If this claim is true, such an effect could be achieved with amantadine and memantine which show neuroprotective activity in animals at therapeutically relevant doses.
Amantadine↗
What is the rationale for new treatment strategies in Alzheimer's disease?
Alzheimer's disease (AD) is characterized by the abnormal extracellular accumulation of amyloid beta-peptide (Abeta) into neuritic plaques and the intraneuronal aggregation of the microtubule-associated protein tau to form neurofibrillary tangles. These molecular events are implicated in the selective damage to neural systems critical for the brain functions that are impaired in AD. Impairment of cholinergic neurotransmission may be an important factor underlying the defects in cognition and memory that characterize AD. Cholinesterase (ChE) inhibitors, such as donepezil, rivastigmine, and galantamine, cause symptomatic improvement by inhibiting the breakdown of the neurotransmitter acetylcholine to increase its synaptic availability and, in the case of galantamine, by also allosterically potentiating nicotinic cholinergic receptors. Other agents, including vitamin E, monoamine oxidase inhibitors, and statins, have shown some benefit in epidemiological studies and clinical trials although compelling evidence of their efficacy is lacking. Memantine, shown to cause cognitive and functional improvement, is not an ChE inhibitor and does not interact with marketed ChE inhibitors. While the mechanism of action of memantine in AD is not known, the principal pharmacologic actions at therapeutic dose are inhibition of ionotropic neurotransmitter receptors, specifically N-methyl-D-aspartate (NMDA), 5-HT3, and nicotinic receptors. Like other NMDA antagonists, memantine causes behavioral activation associated with enhanced cerebral glucose utilization. Studies have shown that memantine can reverse the decreased metabolic activity associated with AD, possibly accounting for its beneficial effects on cognition and global functioning. Memantine also has neuroprotective properties and can inhibit Abeta-induced neurodegeneration.
Acetylcholine↗
Inhibition of human alpha 7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-D-aspartate receptors.
1. Human alpha 7 nicotinic acetylcholine (ACh) receptors were expressed in Xenopus oocytes and the effects of the N-methyl-D-aspartate (NMDA) receptor open channel blockers memantine and cerestat on this receptor were examined using two-electrode voltage-clamp recordings and 125I-alpha-bungarotoxin (125I-alpha-bgtx) binding. 2. Memantine and cerestat produced complete inhibition of ACh-induced inward currents with affinities similar to that reported for native NMDA receptors. Cerestat, IC50 1.7 (-1; +2) microm, was more potent than memantine, IC50 5 (-3;+8) microM, and the effects of both drugs were fully and rapidly reversible. 3. Inhibition of alpha 7 receptor function was voltage-independent, and it occurred at concentrations far lower than those needed to inhibit (never completely) binding of 125I-alpha-bgtx to alpha 7 receptors, suggesting that the effects of memantine or cerestat are noncompetitive. 4. These results provide evidence that human alpha 7 receptors are inhibited by memantine and cerestat and suggest that caution should be applied when using these compounds to study systems in which NMDA and nACh receptors co-exist.
Acetylcholine↗