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PubMed1997

Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat.

Neuropathic pain remains a significant clinical problem. Current understanding implicates the spinal cord dorsal horn N-methyl-d-aspartate (NMDA) receptor apparatus in its pathogenesis. Previous reports have described NMDA antagonist reduction of nerve injury-induced thermal hyperalgesia and formalin injection-related electrical activity. We examined a panel of spinally administered NMDA antagonists in two models: allodynia evoked by tight ligation of the fifth and sixth lumbar spinal nerves (a model of chronic nerve injury pain), and the formalin paw test (a model wherein pretreatment with drug may preempt the development of a pain state). A wide range of efficacies was observed. In the nerve injury model, order of efficacy (expressed as percent of maximum possible effect +/- S.E.), at the maximum dose not yielding motor impairment, was memantine (96 +/- 5%) = AP5 (91 +/- 7%) > dextrorphan (64 +/- 11%) = dextromethorphan (65 +/- 22%) > MK801 (34 +/- 8%) > ketamine (18 +/- 6%). For the formalin test, the order of efficacy was AP5 (86 +/- 9%) > memantine (74 +/- 5%) > or = MK801 (67 +/- 16%) > dextrorphan (47 +/- 16%) > dextromethorphan (31 +/- 12%) > ketamine (17 +/- 15%). In the nerve injury model, no supraspinal action was seen after intracerebroventricular injections of dextromethorphan and ketamine. NMDA antagonists by the spinal route appear to be useful therapeutic agents for chemically induced facilitated pain as well as nerve injury induced tactile allodynia. It is not known what accounts for the wide range of efficacies.

2-Amino-5-phosphonovalerate↗
PubMed2006

Association between amantadine and the onset of dementia in Parkinson's disease.

The objective of this study is to compare the occurrence of dementia among Parkinson's disease (PD) patients treated with amantadine (AM group) with those never exposed to it (NoAM group). PD dementia shares neuroanatomical and biochemical similarities with Alzheimer's disease (AD). Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist has been shown to be beneficial in AD. Memantine is a dimethyl derivative of amantadine, which also possesses NMDA receptor blocking properties. We hypothesized that amantadine could have a beneficial effect on the occurrence of PD dementia. PD patients attending the Movement Disorders Clinics in Hillel Yaffe, Asaf Harofe Medical Centers (Israel) and Pisa (Italy) were included. Taking the onset of dementia as the endpoint, survival curves for AM and NoAM patients were estimated by the Kaplan-Meier method. The study population consisted of 593 patients (age, 69.5 +/- 9.9 years; PD duration, 9.2 +/- 6.0 years; 263 patients (44%) amantadine treated). The endpoint of dementia was reached by 116 patients (20%). PD duration until dementia was significantly longer for AM patients (9.1 +/- 5.7 years) than for NoAM patients (5.9 +/- 4.6 years, P = 0.006). The duration of amantadine exposure positively correlated with PD duration until dementia (P = 0.0001). Survival analysis, taking dementia onset as endpoint, showed slower mental decline in AM patients (Log rank P = 0.0049, Wilcoxon P = 0.0024). Mini-Mental State Examination scores were significantly higher for AM patients than for the NoAM group (P = 0.01). Age of PD onset also significantly influenced the duration of PD until dementia. Amantadine use may delay the onset of dementia in PD patients and may attenuate its severity.

Aged↗
PubMed1984

Evidence for presynaptic antagonism by amantadine of indirectly acting central stimulants.

In mice, amantadine pretreatment (150 mg/kg, but not 10 mg/kg, 2 h prior to testing) markedly inhibited the locomotor stimulation produced by submaximal doses of d-amphetamine, amfonelic acid, methylphenidate, caffeine, memantin, phencyclidine, and cocaine. A 50-mg/kg dose was ineffective in blocking the effects of caffeine and memantin, but blocked the responses to the other five stimulants. Amantadine did not modify the locomotor stimulant effect of apomorphine in reserpinized mice. These results indicate that amantadine acts as a presynaptic antagonist to the above seven stimulants. Even the highest dose of amantadine did not modify the hyperactivity induced in mice by morphine and levorphanol. This result is consistent with evidence showing opiate actions at postsynaptic striatal neurons, sites where presumably amantadine is unable to exert an antagonist effect. Amantadine did not modify the central depressant effects of ethyl alcohol and pentobarbital. Amantadine could be of value as a pharmacological tool in understanding the mode of action of central stimulants, and in the management of stimulant abuse. The present data do not support the currently held view that the antiparkinsonism effect of amantadine results from its ability to potentiate the central effects of dopamine.

Amantadine↗
PubMed1997

6-Hydroxydopamine lesion of locus coeruleus and the antiparkinsonian potential of NMDA-receptor antagonists in rats.

Behavioral and neurochemical effects after bilateral 6-hydroxy-dopamine locus coeruleus- (LC) lesion were examined in rats and compared to sham-lesioned controls. Behavior after treatment with the antiakinetic drugs dizocilpine, amantadine, memantine or L-DOPA as well as joint treatment of these drugs with haloperidol were tested in an open field with holeboard and in an experimental chamber. Under saline spontaneous activity (open field with holeboard) and sniffing (experimental chamber) were reduced after lesion. Injection of the proparkinsonian drug haloperidol decreased sniffing in all rats but to a greater extent in LC-lesioned rats. In combination with haloperidol none of the tested drugs could completely compensate for the motor deficits induced by the lesion. Neurochemical data revealed a reduced content of noradrenaline in the prefrontal cortex and in the posterior striatum of LC-lesioned rats. These results indicate that loss of LC neurons intensifies parkinsonian symptoms induced by blockade of dopamine D2-receptors, and lowers the antiakinetic potential of dizocilpine, amantadine, memantine or L-DOPA.

Adrenergic Agents↗
PubMed2002

Restorative effects of glutamate antagonists in experimental parkinsonism.

Several compounds with antagonistic actions on N-methyl-D-aspartate (NMDA) receptors were tested for an antiakinesic action in hypoactive MPTP-treated C57 BL/6 mice rendered tolerant to the motor activity enhancing effects of the 20 mg/kg, s.c., dose of L-Dopa; each compound was administered 60 min before the administration of the dopamine precursor. The classes of compounds studied included the noncompetitive NMDA antagonists, memantine, amantadine and MK-801, the competitive NMDA antagonist, CGP 40116, the anticonvulsive and putative anticonvulsive agents, lamotrigine and FCE 26743, with a partial glutamatergic antagonistic action. All six compounds elevated locomotor, rearing and total activity counts of L-Dopa-tolerant mice in co-administration with L-Dopa in dose-specific or dose-dependent manners but only memantine and MK-801 affected motor activity in the control mice, that also received chronic L-Dopa treatment. Thus, the restorative actions of those compounds in suprathreshold L-Dopa-tolerant MPTP-treated mice subjected to "wearing-off" of L-Dopa efficacy were assessed in a series of experiments. Within each class of potentially therapeutic agents a differential restorative efficacy of the motor activity-stimulating effects of hypoactive MPTP mice was obtained, confirming the putative antiparkinsonian applications of compounds with glutamate antagonistic actions.

Animals↗
PubMed2006

NGP1-01 is a brain-permeable dual blocker of neuronal voltage- and ligand-operated calcium channels.

Calcium overload of neurons leads to cell death and is a key feature in neurodegenerative diseases. The polycyclic amine NGP1-01 blocks L-type voltage operated calcium channels in cardiomyocytes. Here, we tested whether NGP1-01 blocks neuronal calcium channels. NGP1-01 (1 microM) inhibited depolarization-induced calcium influx by 78% in cortical neurons preloaded with fura-2 AM, with a potency similar to nimodipine. NGP1-01 (1 microM) also inhibited N-methyl-D: -aspartate (NMDA)-induced (1 mM) calcium influx by 52%, only slightly less potent than memantine. Using in vivo-microdialysis, we monitored choline release during NMDA infusion as a measure of excitotoxic membrane breakdown. Intraperitoneal injection of NGP1-01 (40 mg/kg) reduced NMDA-induced membrane breakdown by 31% (P < 0.01) while memantine (10 mg/kg) reduced choline release by 40%. Our results demonstrate that NGP1-01 simultaneously blocks both major neuronal calcium channels and is sufficiently brain-permeable. We conclude that NGP1-01 is a promising lead structure for a new class of dual-mechanism neuroprotective agents.

Animals↗
PubMed1995

Striatal NMDA receptor subtypes: the pharmacology of N-methyl-D-aspartate-evoked dopamine, gamma-aminobutyric acid, acetylcholine and spermidine release.

We have examined the inhibitory potencies of MK 801, memantine, dextromethorphan, Mg2+ and of strychnine-insensitive glycine site antagonists on the N-methyl-D-aspartate (NMDA)-evoked (300 microM) release of [14C]acetylcholine and [3H]spermidine or [14C] gamma-aminobutyric acid [14C]GABA and [3H]dopamine from rat striatal slices. MK 801, dextromethorphan and all glycine antagonists examined (7-chlorokynurenate, L-689,560 ((+/-)-trans-2-carboxy-5,7-dichlorotetrahydroquinoline-4-phenylure a), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dichloroquinoxaline-2,3-dione (DNQX), and (+)-HA966 ((3-amino-1-hydroxypyrrolidin-2-one) more potently inhibited NMDA-evoked dopamine and GABA release than acetylcholine and spermidine release by a factor of 3-21. MgCl2, which does not inhibit NMDA-evoked spermidine release, and memantine which only weakly antagonised NMDA-evoked spermidine release, inhibited NMDA-evoked dopamine, acetylcholine and GABA release with similar potencies. No pharmacological differences were observed between NMDA-evoked dopamine and GABA release. These findings extend those suggesting that NMDA-evoked acetylcholine and spermidine release are mediated by different NMDA receptor subtypes in the striatum and suggest a third native subtype with a distinct pharmacology that regulates striatal dopamine and GABA release.

Animals↗
PubMed1995

Different binding affinities of NMDA receptor channel blockers in various brain regions--indication of NMDA receptor heterogeneity.

The N-methyl-D-aspartate (NMDA) receptor-channel complex exists in multiple forms which probably have different physiological and pharmacological properties. To further evaluate this concept of different NMDA receptor subtypes, receptor binding and autoradiographic techniques were used to study the phencyclidine (PCP) binding site of the NMDA receptor ion-channel complex. [3H]MK-801 was employed to characterize binding properties of (+)-MK-801, (-)-MK-801, phencyclidine (PCP), (+/-)-ketamine, amantadine (1-amino-adamantane) and memantine (3,5-dimethyl-1-amino-adamantane) in different brain regions. Saturation experiments on homogenized membranes revealed the existence of single classes of binding sites in cortex and cerebellum but with significant different affinities between these regions (KD/Cortex = 4.59 nM, Bmax/Cortex = 0.836 pmol/mg protein; KD/Cereb. = 25.99 nM, Bmax/Cereb. = 0.573 pmol/mg protein) suggesting that the lower affinity in cerebellum indicates another population of NMDA receptor channels. In contrast, in striatum there was clear evidence for two binding sites (KD/high = 1.43 nM, Bmax/high = 0.272 pmol/mg protein; KD/low = 12.15 nM, Bmax/low = 1.76 pmol/mg protein). Displacement studies (autoradiography and binding) revealed a lower affinity for unlabeled (+)-MK-801 in striatum which was clearly not the case for memantine. In cerebellar membranes there was a significant decrease in the affinity for both MK-801 enantiomers and PCP but not for the 1-amino-adamantanes. In contrast, all compounds showed lowered affinity in the dentate gyrus. These findings support NMDA receptor heterogeneity which may be of particular relevance for the development of subtype-selective drugs.

Animals↗
PubMed1994

Glutamate antagonists have different effects on spontaneous locomotor activity in rats.

Locomotor activity, ataxia, and stereotypy were assessed in the open field after administration of NMDA and AMPA antagonists acting by different mechanisms. The interaction with glutamatergic receptors was confirmed in the binding assay. (+)MK-801 and phencyclidine (PCP) produced similar changes in horizontal activity, i.e., a strong increase from the beginning of the test. Ketamine, and to a lesser extent, memantine, enhanced horizontal activity at the later observation periods only. Amantadine and NBQX produced a slight inhibition, while GYKI-52466, d-cycloserine, (+R)-HA-966, CGP-37849, and dextromethorphan were ineffective. Vertical activity (rearings) were inhibited by most agents except GYKI-52466 and gly-B partial agonists. At higher doses ataxia was seen after: MK-801, PCP, ketamine, memantine, amantadine, CGP-37849, dextromethorphan, and GYKI-52466. Hence, the inhibition of NMDA and AMPA receptors by agents acting at different recognition sites produces qualitatively different behavioral consequences.

Amphetamine↗
PubMed1996

Evidence for native NMDA receptor subtype pharmacology as revealed by differential effects on the NMDA-evoked release of striatal neuromodulators: eliprodil, ifenprodil and other native NMDA receptor subtype selective compounds.

NMDA increases the release of [14C]acetylcholine and [3H]spermidine or of [14C]GABA and [3H]dopamine from rat striatal slices. The pharmacology of these responses suggests that release of dopamine and GABA, acetylcholine, and spermidine is mediated, respectively, by three distinct NMDA receptor subtypes. IC50 values of compounds for the inhibition of dopamine and GABA release were closely matched, suggesting mediation by the same subtype. This receptor was generally more sensitive to all NMDA antagonists tested relative to that controlling acetylcholine or spermidine release (channel blockers, glycine antagonists, competitive antagonists and polyamine antagonists). The receptors controlling acetylcholine and spermidine release were characterised by lower antagonist sensitivity in general, and that controlling spermidine release was further defined by a marked insensitivity to ifenprodil, eliprodil, magnesium, dextromethorphan, dextrorphan, memantine, desipramine and polyamine spider toxins. In binding studies in which the displacement of 2 nM [3H]MK801 was studied in membranes prepared from a number of brain regions (in the presence of saturating concentrations of glutamate, glycine and spermidine) small regional differences in IC50 values were observed for a number of channel blockers, but no compound generated biphasic displacement curves that would allow masking of a particular subtype and it was not possible to detect binding components that were insensitive to memantine, dextrorphan dextromethorphan or desipramine. Ifenprodil produced biphasic displacement curves in the 1-day-old rat cortex and midbrain (with IC50 values of approximately 2 and 70 microM) and both ifenprodil and eliprodil displaced a small proportion (18%) of [3H]MK-801 with high affinity in the adult rat spinal cord. Displacement of [3H]MK801 by these compounds in all other adult brain regions (cortex, striatum, hippocampus, thalamus, pons, medulla, cerebellum) was monophasic and of low affinity. In general the subtype selectivity suggested by the release studies was not mirrored in the binding experiments, probably because of excessive heterogeneity of sites in the membrane preparations and to the subtype selectivity of [3H]MK801 itself.

Animals↗
PubMed1993

Cytoprotective effect of NMDA receptor antagonists on prion protein (PrionSc)-induced toxicity in rat cortical cell cultures.

Rat cortical cells were incubated with the Scrapie prion protein, PrionSc. At concentrations of 3 ng/ml of PrionSc and higher, the viability of the cells decreased significantly after a 12-h incubation period. Simultaneously, the degree of DNA fragmentation increased. In control experiments with antibodies against PrionSc, PrionSc lost its deleterious effect on neurons. PrionSc did not affect the viability of astrocytes. Drugs known to block NMDA receptor channels, such as memantine (1-amino-3,5-dimethyl-adamantane) (Mem), its analogue 1-N-methylamino-3,5-dimethyl-adamantane as well as (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) prevented the effect of PrionSc. Production of PrionSc in the Scrapie prion-infected subclone of N2 a cells (ScN2 a cells) was not affected by memantine. We conclude that antagonists of the NMDA receptor-channel complex (i) abolish the PrionSc-induced neuronal injury in vitro, and (ii) display no influence on the synthesis and/or the processing of PrionSc.

Animals↗
PubMed2005

NMDA glutamate but not dopamine antagonists blocks drug-induced reinstatement of morphine place preference.

The effects of dopaminergic and glutamatergic antagonists on the drug-induced reinstatement of a previously extinguished morphine conditioned place preference (CPP) in mice were evaluated. Following extinction of a place preference induced by morphine (40 mg/kg), a non-contingent injection of the dopaminergic antagonists SCH 23390 (0.125, 0.5 mg/kg), raclopride (0.3, 1.2 mg/kg), haloperidol (0.1, 0.2 mg/kg) and the dopamine (DA) release inhibitor CGS 10746B (1, 10 mg/kg) or glutamatergic NMDA antagonists memantine (10, 20, 40 mg/kg) and MK-801 (0.1, 0.2, 0.3 mg/kg) alone or with 10 mg/kg morphine was given. Neither the dopaminergic nor the glutamatergic antagonists alone reinstated the place preference. Dopamine antagonists failed to block the morphine-induced reinstatement of place preference while memantine and MK-801 blocked it with intermediate and high doses. These results suggest that drug-induced reinstatement of place preference may be largely independent of dopamine and more closely related to glutamatergic neurotransmission.

Analgesics, Opioid↗
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

Differential pharmacological modulation of the spontaneous stimulus-independent activity in the rat spinal cord following peripheral nerve injury.

Peripheral nerve injury is a significant clinical problem that is often difficult to treat. The major clinical symptoms are numbness, tactile and cooling allodynia, hyperalgesias as well as ongoing pain. In animal models of neuropathy, abnormal responses to applied (or evoked) stimuli can be gauged, but spontaneous pain, a major clinical issue, has proved very difficult to assess. In neuropathic animals, spinal neuronal hyperexcitability indicative of peripheral and central changes with high levels of spontaneous neuronal firing has been reported. This latter stimulus-independent firing of sensory neurones may be a measure related to ongoing pain. Two weeks after L5/6 spinal nerve ligation, deep dorsal horn neurones were recorded in halothane-anesthetized rats. The majority of neurones in neuropathic rats showed increased levels of spontaneous firing with irregular firing patterns. We examined and compared the effects of 5 centrally acting pharmacological agents: morphine (i.t. or i.v.), gabapentin, ketamine, memantine and mepyramine on stimulus-independent neuronal firing. This ongoing activity showed high sensitivity to gabapentin (s.c.) and morphine (i.t.) administration, being significantly reduced in a dose-dependent manner. Morphine administered via the systemic route produced modest but non-significant reductions of spontaneous activity. The two NMDA receptor antagonists, ketamine and memantine, and the histamine H1 receptor antagonist, mepyramine, produced minor effects at doses known to be effective on stimulus evoked measures of deep dorsal horn neurones. This may form an electrophysiological basis for the efficacy of gabapentin and spinal morphine on ongoing pain in patients with peripheral neuropathy.

Action Potentials↗
PubMed2005

Role of dopamine and glutamate receptors in cocaine-induced social effects in isolated and grouped male OF1 mice.

Cocaine administration in paired male mice decreases social contacts as well as increases avoidance and flee elements. As dopamine (DA) and glutamate seem to be involved in some of cocaine's effects, an attempt was made to assess whether a range of associated receptors influenced the social impacts of this drug of abuse. The NMDA antagonist memantine (10 and 40 mg/kg); the AMPA antagonist CNQX (1 and 20 mg/kg); the DA release inhibitor CGS 10746b (2 and 8 mg/kg): the DA D1 antagonist SCH 23390 (0.05 and 0.5 mg/kg); and the DA D2/D3 antagonist raclopride (0.03 and 0.3 mg/kg) were administered prior to 25 mg/kg of cocaine and behaviour was evaluated during an encounter between an experimental and a standard opponent in a neutral cage for 10 min. Memantine reverts cocaine-induced social withdrawal and the increase in avoidance and flee, CNQX being effective only in these latter actions. On the other hand, SCH 23390 counteracts the social as well as the defensive action of cocaine, raclopride being effective only in blocking the cocaine-induced increase in avoidance and flee behaviours. In conclusion, although both neurotransmitter systems are involved in the effects of cocaine on social behaviour, NMDA and D1DA receptors seem to have an important role.

Animals↗
PubMed1997

Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy.

The development of neuroprotective agents for the prevention of neuronal loss in acute conditions such as stroke and epilepsy or chronic neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, Huntington's chorea, and motor neuron disease is currently focusing on drugs that inhibit excitatory amino acid neurotransmission or exhibit antioxidant properties. Unfortunately, potent antagonists at the N-methyl-D-aspartate (NMDA) type glutamate receptor, which is thought to mediate excitotoxic neuronal injury, e.g., MK-801 or phencyclidine (PCP), share a high probability of inducing psychotomimetic side effects. Further, these drugs have been associated with acute neurotoxicity in vitro and in vivo, precluding their clinical use. In contrast, low affinity NMDA receptor antagonists like amantadine and its dimethyl derivative, memantine, have been administered clinically for the management of Parkinson's disease, dementia, neuroleptic drug-induced side effects, and spasticity. These agents have only rarely induced significant psychotomimetic side effects. Recent pharmacologic advances have helped to elucidate how high drug affinity for the PCP binding site of the NMDA receptor may enhance psychotogenicity. Low affinity and associated fast voltage-dependent channel unblocking kinetics are likely to be responsible for the better tolerance of amantadine and memantine compared with MK-801 and PCP. Further factors apparently modulating psychotogenicity of glutamate receptor antagonists include differential actions on neuronal populations in various brain regions and interactions with neurotransmitter receptors other than the NMDA type glutamate receptor.

Alzheimer Disease↗
PubMed1998

Differential effects of NMDA and non-NMDA antagonists on the activity of aromatic L-amino acid decarboxylase activity in the nigrostriatal dopamine pathway of the rat.

This study examined the acute effects of a variety of NMDA and non-NMDA antagonists on the activity of aromatic l-amino acid decarboxylase (AADC) in the corpus striatum (CS) and substantia nigra (SN) of the rat. Sixty min pretreatment with the high affinity NMDA receptor-channel blockers MK 801 (0.01, 0.1 and 1 mg/kg) and phencyclidine (4 mg/kg) elevated AADC activity in both the CS and SN (2- to 3-fold). Even more striking increases in AADC were noted with 40 mg/kg amantadine (3.8-fold for CS, 9.0-fold for SN), 40 mg/kg memantine (3.4-fold for CS, 3.1-fold for SN; 20 mg/kg no effect) and 40 mg/kg dextromethorphan (3.4-fold for CS, 6.2-fold for SN, in 6/10 'responders'). Similarly pronounced increases in AADC activity in CS (1.9-fold) and SN (2.8-fold) were detected after administering clonidine (2 mg/kg). R-HA 966 (5 mg/kg, not 1 mg/kg) modestly raised AADC activity in CS (0.45-fold) and not SN. Other drugs had no effect on the activity of the decarboxylase enzyme, including CGP 40116 (1 and 5 mg/g), eliprodil (10 mg/kg), NBQX (10 mg/kg, 30 min pretreatment) and atropine (1 mg/kg). These experiments indicate that blocking the NMDA receptor-channel (and to a lesser extent the glycine site) or stimulating alpha2-adrenoceptors, profoundly increases AADC activity, more especially in the SN than CS. By contrast, inhibiting the NMDA glutamate recognition or polyamine sites, AMPA or muscarinic receptors is without effect on AADC in either brain region. The ability of amantadine and memantine to potentiate the antiparkinsonian actions of l-DOPA in the clinic, may be due to facilitated decarboxylation of l-DOPA by the brain.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2001

NMDA antagonists produce site-selective impairment of accuracy in a delayed nonmatch-to-sample task in rats.

Antagonists at the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor are purported to have detrimental effects on cognitive processes. In order to examine the site selectivity of these effects, phencycline (PCP), dizocilpine, and memantine (PCP-site antagonists), SDZEAA 494 and NPC17742 (competitive NMDA antagonists), ACEA 1021 (glycine-site antagonist), and eliprodil (NR2B-selective polyamine-site selective antagonist) were tested in rats performing a delayed nonmatch-to-sample task. Dizocilpine, PCP and memantine significantly decreased accuracy and discriminability, particularly during brief delay trials. In contrast, the competitive NMDA antagonists, SDZ EAA 494 and NPC 17742, did not affect accuracy or discriminability at any delay. Similarly, ACEA 1021, and eliprodil did not alter behavioral indices in a manner suggesting compromise in information processing at any delay even at doses that decreased the total number of trials completed. These data support previous findings that the effects of NMDA antagonists on accuracy are site-selective, with PCP-site antagonists producing the greatest disruption. Further, while not conclusive, the results are consistent with the hypothesis that NMDA receptor-mediated neurotransmission may be important at early stages of information processing, although further research is necessary to confirm these latter observations.

Animals↗