dizocilpine-maleate and licostinel

NMDA receptor antagonists have been reported to affect learned behaviors conditioned with abused drugs, with the outcome dependent, in part, on the class of NMDA receptor antagonist used. The present study tested the ability of various site-selective NMDA receptor antagonists to modify cocaine-conditioned motor activity. Two procedures were used for independently assessing drug effects on spontaneous activity and expression of cocaine-conditioned behavior. In the conditioning experiments, rats were administered i.p. injections of cocaine (30 mg/kg) or saline paired with distinctive environments. Spontaneous horizontal activity was dose-dependently enhanced by dizocilpine (0.03-0.3 mg/kg) and memantine (1-30 mg/kg), but not by D-CPPene (3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid; SDZ EAA 494; 1-10 mg/kg), ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2, 3-quinoxalinedione; 3-56 mg/kg), or eliprodil (3-30 mg/kg). Higher doses of memantine, D-CPPene (1-10 mg/kg), eliprodil (3-30 mg/kg), or ACEA-1021 reduced vertical activity. Following five cocaine-environment pairings, rats displayed significant increases in motor activity when exposed to the cocaine-paired environment. The following antagonists were administered prior to the conditioning test: dizocilpine (MK-801; 0.03-0.1 mg/kg), memantine (1-10 mg/kg), D-CPPene (0.3-3 mg/kg), ACEA-1021 (3-10 mg/kg), and eliprodil (1-10 mg/kg). Of these, memantine, ACEA-1021 and, to the lesser degree, eliprodil attenuated expression of cocaine-conditioned motor activity at doses that did not significantly affect spontaneous motor activity. These results show that cocaine-conditioned behaviors can be selectively modulated by some, but not all, NMDA receptor antagonists.

Topics: Animals; Cocaine; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Male; Memantine; Motor Activity; Piperazines; Piperidines; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

This study examined the effect of glycine recognition site antagonism (ACEA 1021) on the incidence of spontaneous depolarizations in the penumbra of a focal ischemic lesion. Rats were administered either vehicle (n = 7), ACEA 1021 (n = 7) or dizocilpine (n = 5) and then underwent 90 min middle cerebral artery occlusion. The cortical direct current (DC) potential was recorded. During ischemia, 7 +/- 3 DC shifts occurred in the vehicle group. ACEA 1021 did not reduce this frequency (7 +/- 2 DC shifts) although dizocilpine did (1 +/- 1 DC shifts; p = 0.02). The previously demonstrated neuroprotective property of ACEA 1021 during focal cerebral ischemia cannot be attributed to reduction of spontaneous depolarization in the ischemic penumbra.

Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Male; Membrane Potentials; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, Glycine

NMDA antagonists of glutamate have psychotomimetic side effects and structural side effects which have been shown to be lethal to CNS neurons in the cingulate and retrosplenial cortex of rodents, yet these compounds may reduce focal ischemic brain damage. This investigation used 38 Wistar rats to determine whether the structural toxicologic profile of a newly developed halogenated quinoxalinedione derivative, a pharmacologic antagonist of the glycine site on the NMDA receptor complex, is identical to that seen with MK-801. In the cingulate and retrosplenial cortex, examination of glutaraldehyde perfusion-fixed, plastic-embedded tissue 4 to 6 hours after intravenous administration of 10 mg/kg of the glycine antagonist 5-nitro-6,7-dichloroquinoxalinedione (ACEA-1021), no changes were seen by light or electron microscopy. At a dose of 30 mg/kg, neurons were seen containing 1 to 2 microns granules in perikarya and axons. Vacuolated neurons, as described in NMDA-antagonist neurotoxicity, were exceedingly rare, comprising only 4 in the entire study. Electron microscopy of the granulated profiles showed intracytoplasmic areas containing grouped mitochondria and lysosomes, located in neuronal perikarya, and rarely in myelinated axons. Neuronal necrosis was evaluated in formaldehyde perfusion-fixed, paraffin-embedded tissue at one week survival, and was absent. MK-801 5 mg/kg, in contrast, caused irreversible (necrotizing) neuronal changes. The results demonstrate that this glycine antagonist is devoid of lethal neurotoxicity, but causes a reversible alteration in a small proportion of cingulate and retrosplenial cortical neurons. Since previous studies have shown anti-ischemic efficacy of this compound in focal, but not global ischemia, it appears that the therapeutic profile of this antagonist of the strychnine-insensitive glycine site is similar, but the toxicologic structural profile is different, from NMDA receptor antagonists.

Topics: Animals; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gyrus Cinguli; Male; Microscopy, Electron; Neurotoxins; Quinoxalines; Rats; Rats, Wistar; Receptors, Glycine; Survival Rate

Acute subdural hematoma (SDH) complicates 20% of severe human head injuries and causes death or severe disability in 60% of these cases, due to brain swelling and high intracranial pressure. Although the mechanisms for these phenomena are unknown, previous studies have implicated excitatory amino acid-mediated mechanisms in both humans and animal models. The authors therefore performed in vivo autoradiography using 125I-MK-801, a high-affinity noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, as a tracer to evaluate NMDA ion channel activation spatially and temporally as a factor causing cytotoxic swelling. Acute SDH was induced in 16 anesthetized rats using 0.4 ml autologous venous blood. Fifty microcuries of 125I-MK-801 was injected via an aortic arch cannula 30 minutes after onset of SDH. The effect of a new putatively neuroprotective drug, ACEA-1021, a glycine-specific binding site NMDA antagonist, on 125I-MK-801 binding was tested on five animals "Nonspecific" 125I-MK-801 binding in the rat brain was assessed by pretreatment with "cold" (nonradiolabeled) MK-801 in five more animals. Four hours later the animals were sacrificed and brain sections were apposed to radiation-detecting high-sensitivity photographic film with precalibrated plastic standards for 4 weeks. A striking and highly significant 1.7- to 4.8-fold increase in 125I-MK-801 binding was seen in the penumbra of viable tissue surrounding the ischemic zone beneath the acute SDH, when compared to contralateral hemisphere binding (p < 0.001). The MK-801 pretreatment markedly reduced 125I-MK-801 uptake in this penumbral zone (4.73 +/- 0.36 nCi/mg control vs. 2.85 +/- 0.08 nCi/mg cold MK-801; p < 0.0001), indicating that the increased binding in the penumbra of the lesion was due to NMDA ion channel activation. Pretreatment with ACEA-1021 reduced 125I-MK-801 uptake by 28% (3.41 +/- 0.26 nCi/mg vs. 4.73 +/- 0.36 nCi/mg; p < 0.05), indicating that this agent prevents opening of the NMDA ion channel and, thus, exposure of its receptor for MK-801 binding. These studies show intense foci of penumbral NMDA receptor-mediated ion channel activation after onset of SDH, which is markedly reduced by an NMDA antagonist. Such agents are thus likely to reduce cell swelling after SDH occurs.

Topics: Animals; Autoradiography; Brain; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hematoma, Subdural; Humans; Male; Quinoxalines; Rats; Rats, Sprague-Dawley

Ischemia-induced neuronal injury can be reduced by glutamate antagonists acting at the N-methyl-D-aspartate (NMDA) receptor. 7-Chlorokynurenic acid and the recently synthesized compound Acea 1021 block NMDA receptors by acting at the strychnine-insensitive glycine site. The anti-ischemic properties of these compounds were tested by evaluating their ability to reduce CA1 neuronal damage in hippocampal slice cultures deprived of oxygen and glucose. Acea 1021 and 7-chlorokynurenic acid significantly reduced CA1 injury produced by oxygen and glucose deprivation in a dose-dependent manner. The neuroprotective effect of these compounds was reversed by the addition of glycine. The phencyclidine site NMDA antagonist MK-801 also provided significant protection to CA1 neurons against the same insult, and this protection was not affected by the addition of glycine. These results indicate that Acea 1021 and 7-chlorokynurenic acid can provide protection to CA1 neurons against ischemia-induced injury by a glycine-sensitive mechanism.

Topics: Animals; Brain Ischemia; Cell Death; Dizocilpine Maleate; Glycine; Glycine Agents; Hippocampus; Kynurenic Acid; Neurons; Organ Culture Techniques; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate