NMDA Receptor

Dizocilpine (MK-801) gradually reduces the current that is brought on by NMDA. Even after applying Dizocilpine for an extended period of time in the presence of NMDA, Mg2+ (10 mM) stops Dizocilpine from inhibiting the N-Me-D-Asp-induced current. Dizocilpine inhibits single-channel activity in outside-out patches that is triggered by NMDA[3]. When microglia are activated by LPS, BV-2 cells express more Cox-2 protein, and dizocilpine (MK-801; <500 μM) blocks this process. With an EC50 of 400 μM in BV-2 cells, dizocilpine (<500 μM) decreases microglial TNF-α production[4].

Before each METH injection, mice receive a 1 mg/kg dose of dizocilpine (MK 801), which reduces the amount of DA depletion in the striatum by 55%. Additionally, METH's effects on microglial activation in the mouse striatal membrane are lessened by dizocilpine (MK 801) (1 mg/kg)[4]. ) before two reactivation sessions in the home cage exhibits no suppression on subsequent cocaine-primed reinstatement[5]. Dizocilpine ((+)-MK 801) (0.05, 0.2 mg/kg, ip) attenuates subsequent cocaine-primed reinstatement without disruption in rats.

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In animal modeling, dizocilpine maleate can be used to create models of schizophrenia. Recent research suggests that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Conversely, reconsolidation may be disrupted by certain pharmacological agents such that the drug-associated memory is weakened. Several studies have demonstrated disruption of memory reconsolidation using a drug-induced conditioned place preference (CPP) task, but no studies have explored whether cocaine-associated memories can be similarly disrupted in cocaine self-administering animals after a cocaine priming injection, which powerfully reinstates drug-seeking behavior. Here we used cocaine-induced CPP and cocaine self-administration to investigate whether the N-methyl-D-aspartate receptor antagonist (+)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) given just prior to reactivation sessions would suppress subsequent cocaine-primed reinstatement (disruption of reconsolidation). Systemic injection of MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions [5].

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The effects of five administrations (3- to 4-day intervals) of morphine (MOR: 10 and 20 mg/kg, s.c.) alone, MK-801 (dizocilpine: 0.03, 0.1, 0.3 and 1 mg/kg, i.p.) alone, and combinations of MOR with MK-801 on the ambulation in mice were investigated. MK-801 at 0.3 and 1 mg/kg, but not at 0.03 and 0.1 mg/kg, significantly increased the ambulation of mice. Although the mice given repeated administrations of MK-801 (0.3 and 1 mg/kg) exhibited enhancement and reduction, respectively, in the ambulation-increasing effect of the individual doses, they showed significantly higher sensitivity than the saline-treated mice to the challenge with MOR (10 mg/kg). The repeated administrations of MOR (10 and 20 mg/kg) induced a progressive enhancement of the ambulation-increasing effect. The mice repeatedly given MOR (10 mg/kg) exhibited significant increase in the sensitivity to MK-801 (0.03-0.3 mg/kg). The coadministrations of MOR with MK-801 intensified the ambulation-increasing effect, and repeated coadministrations induced progressive enhancement of the effect, except for the combinations of MOR (10 or 20 mg/kg) with MK-801 (1 mg/kg). However, the induction of MOR sensitization was not modified by any doses of MK-801, except for the case of combination of MOR (20 mg/kg) with MK-801 (1 mg/kg) which was highly toxic (i.e., eliciting death or a moribund condition). On the other hand, simultaneous treatment with SCH 23390 (0.05 mg/kg, s.c.) or nemonapride (0.05 mg/kg, s.c.), or 4-hr pretreatment with reserpine (1 mg/kg, s.c.) strongly, and 4-hr pretreatment with alpha-methyl-p-tyrosine (200 mg/kg, i.p.) partially reduced the ambulation-increasing effect of both MOR (10 mg/kg) and MK-801 (0.3 mg/kg). Simultaneous treatment with naloxone (1 mg/kg, sc) selectively reduced the effect of MOR. However, simultaneous treatment with apomorphine (0.1 mg/kg, s.c.) did not modify the effects of either drug. These results suggest that the characteristics of the ambulation-increasing effects of MOR and MK-801 are similar to each other, and that the repeated treatments with MK-801 induce a cross-sensitization to MOR and vice versa[6].

The compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate)] is a potent anticonvulsant that is active after oral administration and whose mechanism of action is unknown. We have detected high-affinity (Kd = 37.2 +/- 2.7 nM) binding sites for [3H]MK-801 in rat brain membranes. These sites are heat-labile, stereoselective, and regionally specific, with the hippocampus showing the highest density of sites, followed by cerebral cortex, corpus striatum, and medulla-pons. There was no detectable binding in the cerebellum. MK-801 binding sites exhibited a novel pharmacological profile, since none of the major neurotransmitter candidates were active at these sites. The only compounds that were able to compete for [3H]MK-801 binding sites were substances known to block the responses of excitatory amino acids mediated by the N-methyl-D-aspartate (N-Me-D-Asp) receptor subtype. These comprised the dissociative anesthetics phencyclidine and ketamine and the sigma-type opioid N-allylnormetazocine (SKF 10,047). Neurophysiological studies in vitro, using a rat cortical-slice preparation, demonstrated a potent, selective, and noncompetitive antagonistic action of MK-801 on depolarizing responses to N-Me-D-Asp but not to kainate or quisqualate. The potencies of phencyclidine, ketamine, SKF 10,047, and the enantiomers of MK-801 as N-Me-D-Asp antagonists correlated closely (r = 0.99) with their potencies as inhibitors of [3H]MK-801 binding. This suggests that the MK-801 binding sites are associated with N-Me-D-Asp receptors and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant[1].

Neurons were dissociated from the visual cortex of 2- to 6-day-old Long Evans rat pups and grown in culture for 5-43 days as described (21). Currents activated by excit-fory amino acids were measured in the whole-cell and outside-out patch-clamp configurations. Pipettes contained an internal solution (in mM) of 120 cesium methanesulfonate, 5 CsCI, 10 Cs2EGTA, 5 Mg(OH)2, 5 MgATP, 1 Na2GTP, and 10 Hepes (pH adjusted to 7.4 with CsOH). The external solution (in mM) was 160 NaCl, 2 CaC12, and 10 Hepes (pH 7.40). In whole-cell experiments, 300 nM tetrodotoxin and 10 kLM bicuculline methiodide were added to the external solution to suppress spontaneous activity. MK-801, the kind gift of Paul Anderson, was added from stock solutions of 2-50 mM in ethanol, stored at - 20'C. Final concentrations of ethanol were <0.1%. Cells or patches were bathed in control or agonist-containing external solution flowing from one of a linear array of 7-10 microcapillary tubes fed by gravity. Rapid solution changes were made by moving the array of tubes relative to the cell (whole-cell) or by moving the pipette relative to the tubes (patch). All experiments were done at 20-250C[3].

\n\nSystemic injection of Dizocilpine/MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions.[5]

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\n\nSubjects [5]
\nMale Sprague-Dawley and Long-Evans Hooded rats weighing 280–350 g at the start of the experiment were housed in a temperature- and humidity-controlled colony room with a 12-h light/dark cycle (lights on at 6:00 a.m.). Sprague-Dawley rats were used for all CPP studies, and our initial self-administration studies used Long-Evans rats because of their higher general activity levels and thus higher initial lever pressing during acquisition of the self-administration task. However, to ensure that there were no strain differences in the effects of Dizocilpine/MK-801 on self-administration behavior, we also used Sprague-Dawley rats to test the effects of the highest dose of MK-801 compared with Saline vehicle in this strain. No significant differences were found for the effects of MK-801, so the data from both strains were pooled. Animals undergoing self-administration were housed in a 12-h reverse light/dark cycle (lights on at 6:00 p.m.). Experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and experimental protocols were approved by the University Animal Care and Use Committee. Animals were housed two per cage for the CPP studies and individually for the self-administration studies. Food and water were provided ad libitum except for when animals were engaged in experiments.\n

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\nDrug administration [5]
\n \nDizocilpine(+)-MK-801 hydrogen maleate was dissolved in sterile saline for i.p. injection (1 mL/kg). The doses chosen were 0.05 and 0.20 mg/kg, based on previous work by Przybyslawski and Sara (1997).\n

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\nSurgery [5]
\nSelf-administration surgery was conducted according to a modification of McFarland and Kalivas (2001). Rats were anesthetized with zyket (ketamine 87 mg/kg + xylazine 13 mg/kg) given intramuscularly prior to implanting a chronic indwelling i.v. catheter. The catheter was surgically implanted into the right jugular vein, and the distal end was led subcutaneously to the back between the scapulas. Catheters were constructed from Silastic tubing (9 cm; inner diameter 0.025 in, outer diameter 0.047 in) connected to a back-mount cannula pedestal, a bent 22-gauge metal cannula encased within a plastic screw connector attached to a polyester mesh (Plastics One). A small ball of silicone sealant was placed ∼2.8 cm from the end of the catheter. The right jugular vein was isolated, the most anterior portion of the vein was tied shut, and a small incision was made. The distal end of the catheter was inserted into the vein until the silicone ball was flush with the vein. The vein was secured by tying suture thread on both sides of the silicone ball; additionally, the thread on both sides was tied together. Immediately after surgery, the catheter was injected with 0.1 mL of locking solution: heparin (500 U/mL), gentamicin (5 mg/mL), and glycerol (60%) in sterile saline. Incisions were sutured, and the animal was given 5–7 d to recover. After surgery, the catheter was flushed daily with 0.1 mL of heparin (10 U/mL) and gentamicin antibiotic (5 mg/mL) in sterile saline to help protect against infection and catheter occlusion.\n

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\nBehavioral procedures [5]
\nCPP [5]
\nAll CPP studies were conducted during the same time of day. The proposed studies employed a three-compartment CPP apparatus as previously described (Brown et al. 2007). Briefly, the procedure consisted of a preconditioning preference test, training for 8 d (4 saline pairings alternating with 4 cocaine pairings), testing for CPP acquisition followed by extinction sessions, and cocaine-primed reinstatement with a 10 mg/kg, i.p. dose of cocaine (Brown et al. 2007). Except for the training days, rats had access to all three compartments of the CPP apparatus.\n

\nIn Experiment 1, we tested whether Dizocilpine/MK-801 would impair reconsolidation of the memory for the cocaine-associated context during reinstatement testing. Animals underwent preconditioning, conditioning, testing, and extinction as described above, and on Reactivation Day 1, rats received saline or MK-801 (0.05 mg/kg or 0.20 mg/kg, i.p.) 30 min prior to a cocaine injection (10 mg/kg, i.p.) and placed immediately into the central compartment of the CPP box (Reactivation Day 1). Rats were allowed to explore all three compartments. The next day, the procedure from Reactivation Day 1 was repeated (Reactivation Day 2). This procedure was given for 2 d because our previous studies using a different pharmacological agent (Brown et al. 2007) indicated that one day of memory reactivation was not sufficient to disrupt subsequent cocaine-primed reinstatement. The following day, animals were tested for cocaine-primed reinstatement without any prior injection of either saline or MK-801 before being placed into the CPP box (Reinstatement Day). Rats were allowed to explore all three compartments.\n

\nExperiment 2 was identical to Experiment 1 with the exception of the cage location where Dizocilpine/MK-801 and cocaine injection took place on Reactivation Days 1 and 2. In Experiment 2, animals were given saline or MK-801 followed by cocaine 30 min later in the home cage instead of in the CPP apparatus for the two days of “reactivation.” This was done to determine whether reactivation of the memory for the cocaine-associated context by cocaine in the CPP context was necessary for the ability of MK-801 to disrupt reconsolidation. Animals underwent preconditioning, conditioning, testing, and extinction as described above but animals were injected with saline or MK-801 (0.20 mg/kg, i.p.) 30 min prior to a cocaine injection (10 mg/kg, i.p.) in the home cage. Animals remained in the home cages, and the next day, the procedure from the first day of reactivation was repeated. The following day, animals were tested for cocaine-primed reinstatement in their CPP box without any prior microinjection of saline or MK-801, exactly as described for the Reinstatement Day in Experiment 1 above.

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Dissolved in saline; 0.1mg/kg; oral gavage

Male Sprague-Dawley rats

Dezocepine (MK-801) is a non-competitive NMDA receptor antagonist with high binding affinity, requiring an open pathway to block the receptor. Key pharmacokinetic characteristics include:
1. Bioavailability and Absorption
o Although specific bioavailability data for dezocepine are not available in the literature, its structural analogue, olphenadrine (an NMDA receptor antagonist with similar properties), has been shown to cross the blood-brain barrier, suggesting that dezocepine may also possess this property.
2. Metabolism and Elimination
o Studies in Reeler mice have shown that the efficacy of dezocepine is associated with GABAergic regulation, suggesting that it may be metabolized in the liver, which is involved in neurotransmitter pathways.
o Comparative pharmacokinetic data from paliperidone derivatives indicate that some drugs targeting the central nervous system may be rapidly metabolized, but the exact metabolic profile of dezocepine remains unclear.
3. Pharmacodynamic Interactions
o In the synaptic plasticity dysfunction model, dezoceppine exhibited enhanced NMDA receptor blocking, suggesting that the pharmacokinetic-pharmacodynamic relationship is context-dependent.
Further data beyond the current search results are needed for precise quantification (e.g., T_max, half-life).

Interactions
This study aimed to investigate the effects of the non-competitive NMDA glutamate receptor antagonist dezoceppine maleate (MK-801) on the neurotoxic effects of long-term high-dose dexamethasone (DEX). Results showed that DEX (120 mg/kg/day, for 7 consecutive days) impaired long-term memory and motor coordination in mice, reduced body weight, and led to death. Morphological and ultrastructural studies confirmed that long-term use of DEX alone caused hippocampal neuronal damage, particularly in the CA3 region. Damaged pyramidal neurons exhibited significant nuclear morphological changes and cytoplasmic condensation. MK-801 alone (non-toxic dose 0.3 mg/kg/day) did not alter mouse behavior or hippocampal neuronal morphology. However, it did not prevent the neurotoxic effects of DEX. Instead, it exacerbated dexamethasone (DEX)-induced neurotoxicity. In a preliminary study, a dose of 2.5 mg/kg methamphetamine (METH) instead of 1.0 mg/kg induced a delayed increase in glutamate levels in the nucleus accumbens (NAc). The study hypothesized that repeated increases in glutamate levels lead to behavioral sensitivity to the selective, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dezocephalin (MK-801), and that activation of protein kinase C (PKC) plays a crucial role in this sensitivity. This study aimed to confirm the delayed increase in glutamate levels induced by a higher dose of METH (2.5 mg/kg) and to examine the effect of the PKC inhibitor astrococcus on the dezocephalin sensitivity induced by a higher dose of METH. A dose of 2.5 mg/kg of methamphetamine (METH), instead of 1.0 mg/kg, induced a delayed increase in glutamate levels. Acute administration of astrococcus following a single injection of METH (2.5 mg/kg) did not affect motor activity. Repeated administration of METH (2.5 mg/kg, every other day for a total of five times) induced behavioral sensitivity in mice to the motor-induced effects of the selective, non-competitive NMDA receptor antagonist dezocephalin (0.2 mg/kg). Administration of astrococcus (0.1 mg/kg) 120 minutes after each METH administration inhibited the development of behavioral sensitivity to dezocephalin. …These results suggest that elevated glutamate levels and protein kinase C (PKC) activation are involved in delayed induced synaptic and cellular plasticity, which is a potential mechanism for high-dose methamphetamine (METH)-induced behavioral sensitivity to dezocephalin. …This study aimed to investigate the importance of sex differences in the interaction between dezocephalin (MK-801) pretreatment and acute cold restraint stress (CRS) on pentylenetetrazole (PTZ)-induced seizures in albino Swiss mice. ...This study used the CRS protocol to investigate the interaction between MK-801 pretreatment (30 minutes before CRS) and stress (followed by PTZ injection) on susceptibility to epilepsy. Mice were divided into six groups: (1) PTZ control group (received PTZ only); (2) stress group (received stress and PTZ); (3) saline group (received saline and PTZ); (4) MK-801 group (received MK-801 and PTZ); (5) saline + stress group (received saline, stress, and PTZ); and (6) MK-801 + stress group (received MK-801, stress, and PTZ). ...Pretreatment with MK-801 (0.125, 0.25, 0.50 mg/kg) significantly enhanced the protective effect of stress against PTZ (65 mg/kg)-induced seizures and prolonged the duration of myoclonic and clonic seizures in both male and female mice. Compared with female mice in all groups (PTZ control, stress group, saline group, MK-801 group, saline + stress group, and MK-801 + stress group), the onset time of myoclonus (male: 66.7–295.5 seconds; female: 54.0–247.5 seconds; P < 0.05) and clonic seizures (male: 123.5–789.8 seconds; female: 94.5–757.2 seconds; P < 0.05) was significantly delayed in male mice. …The findings in mice suggest that sex hormones are involved in the interaction between MK-801 pretreatment and PTZ-induced acute CRS. …Adolescent male Wistar rats were exposed to ethanol vapor daily for 12 hours for 5 weeks. Eight weeks after alcohol withdrawal, the effects of intraperitoneal injection of MK-801 (0.0 to 0.1 mg/kg) on electroencephalography (EEG) and auditory event-related potentials (ERPs) were evaluated. …Adolescent alcohol exposure reduced EEG variability in the 4–6 Hz frequency band of the frontal cortex, but had no effect on EEG power or ERPs in the cortex and hippocampus. …After adolescent alcohol exposure, MK-801 significantly reduced EEG power in the parietal cortex (4–6 Hz, 6–8 Hz, 8–16 Hz, 16–32 Hz) and hippocampus (16–32 Hz), as well as EEG variability in the parietal cortex (6–8 Hz, 16–32 Hz). MK-801 significantly reduced hippocampal EEG variability (4–6 Hz, 8–16 Hz, 16–32 Hz) in control rats, but this phenomenon was not observed in the ethanol-exposed rats. Compared to the control group, MK-801 reduced the amplitude and latency of frontal P1 event-related potentials (ERPs) in response to rare tones in ethanol-exposed rats. Conversely, MK-801 significantly reduced the amplitude and latency of P3 ERPs in control rats, but this was not observed in ethanol-exposed rats. The conclusion is that after prolonged withdrawal following ethanol exposure in adolescence, the effects of MK-801 on hippocampal EEG variability and the amplitude and latency of P3 ERPs are significantly reduced. However, in rats exposed to ethanol in adolescence, the inhibitory effect of MK-801 on cortical and hippocampal EEG power is enhanced. Taken together, these data suggest that the NMDA system undergoes long-term changes following alcohol exposure in adolescence.
For more (complete) data on interactions of dezoceppine (39 in total), please visit the HSDB records page.

[1]. The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986 Sep;83(18):7104-8.

[2]. Convergent Strategy to Dizocilpine MK-801 and Derivatives. J Org Chem. 2018 Apr 6;83(7):4264-4269.

[3]. Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1307-11.

[4]. MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity. Brain Res. 2005 Jul 19;1050(1-2):190-8.

[5]. The NMDA antagonist MK-801 disrupts reconsolidation of a cocaine-associated memory for conditioned place preference but not for self-administration in rats. Learn Mem. 2008 Dec 2;15(12):857-65.

[6]. Modification by MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist sensitization: evaluation by ambulation in mice. Nihon Shinkei Seishin Yakurigaku Zasshi. 1996 Feb;16(1):11-8.

[7]. Decrease of growth and differentiation factor 10 contributes to neuropathic pain through N-Me-D-Asp receptor activation. Neuroreport. 2017 May 24;28(8):444-450.

Dezocephalin is an organic heterotetracyclic compound with the structure 1-methyl-8-azabicyclo[3.2.1]octane, fused with two benzene rings at the 2-3 and 6-7 ortho positions (5S,10R-stereoisomers). It is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, affecting cognitive function, learning, and memory. It has a variety of pharmacological effects, including NMDA receptor antagonist, anesthetic, anticonvulsant, nicotine receptor antagonist, and neuroprotective agent. It is a secondary amine compound and a tetracyclic antidepressant, and is the conjugate base of dezocephalin(1+). A potent non-competitive antagonist of the NMDA receptor (receptor, N-methyl-D-aspartate), it is primarily used as a research tool. This drug has been considered for the treatment of various neurodegenerative diseases or disorders in which the NMDA receptor may play an important role. Due to its psychoactive effects, the use of this drug is mainly limited to animal and tissue experiments.

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Mechanism of Action
This study investigated the effects of systemic administration of levodopa or MK-801 on the mRNA levels of glutamate decarboxylase 65 and 67 kDa subtypes (GAD65 and GAD67) in the striatum and globus pallidus (GP). These rats were diagnosed with hemilateral Parkinson's disease via intrastantial injection of 6-hydroxydopamine in the substantia nigra. GAD mRNA levels were assessed using in situ hybridization histochemistry. In the striatum, dopamine denervation led to elevated GAD67 mRNA levels in both the cephalic and caudal regions, while GAD65 mRNA levels were selectively elevated only in the caudal region. Levodopa and MK-801 treatments had different effects on the levels of the two GAD subtypes in 6-hydroxydopamine-injured rats. Levodopa enhanced the injury-induced increase in GAD67 transcripts, while MK-801 had no such effect; conversely, MK-801 inhibited the increase in GAD65 transcripts, while levodopa had no such effect. These data indicate heterogeneity in glutamate-dopamine interactions in the anterior and posterior striatal regions and suggest that NMDA-mediated mechanisms are involved in 6-hydroxydopamine-induced changes in striatal GAD65 transcription, but not in GAD67 transcription. In the globus pallidus (GP), 6-hydroxydopamine injury elevates both GAD65 and GAD67 mRNA levels. Levodopa or MK-801 treatment inhibited the injury-induced elevation of both GAD mRNA levels. These results suggest that dopamine denervation-induced alterations in globus pallidus neuronal functional activity involve dopamine and glutamate NMDA receptor-mediated mechanisms. A comparison of the effects of levodopa and MK-801 treatment on markers of striatal and globus pallidus GABAergic neuronal activity further indicates that the effects of these treatments on pallidus levels are not entirely dependent on the striatum-pallidus pathway.

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Therapeutic Use
/EXPL/ Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists have been found to have potent anti-inflammatory effects and are considered potential therapies for treating cerebral ischemia. Glutamate is the most common excitatory neurotransmitter in the central nervous system and is excessively released during ischemia. Since no single drug class has yet been proven effective in humans, stroke treatment requires the use of multiple drugs in combination. This study aimed to evaluate whether treatment with the N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801) could improve recovery from ischemic brain injury, and whether the PPAR-γ ligand rosiglitazone could enhance its neuroprotective effects in an embolic stroke model. Stroke was induced in rats using a pre-formed thrombus embolization of the middle cerebral artery. Immediately after embolization, rosiglitazone (0.1 mg/kg) was administered intraperitoneally, followed by intravenous injection of MK-801 (0.1 mg/kg). Forty-eight hours later, brain tissue was harvested, sectioned, stained with triphenyltetrazolium chloride, and analyzed using commercial image processing software. The results showed that rosiglitazone, MK-801, alone or in combination, reduced infarct volume by 49.16%, 50.26%, and 81.32%, respectively (P < 0.001). Furthermore, the combination therapy significantly reduced infarct volume compared to any single-agent treatment (P < 0.05). MK-801 reduced cerebral edema by 68% compared to the control group (P < 0.05), but neither rosiglitazone nor the combination therapy showed significant efficacy. Both single-agent and combination therapies improved neurological function, but the combination therapy was more effective in improving neurological deficits. The data suggest that the combination of MK-801 and rosiglitazone has a stronger neuroprotective effect in thromboembolic stroke than single-agent therapy; this effect may represent a potential additive effect in cerebral infarction. Dezoceppine maleate is a maleate salt prepared by reacting dezoceppine with an equivalent amount of maleic acid. It possesses anesthetic, anticonvulsant, neuroprotective, nicotine receptor antagonist, and NMDA receptor antagonist effects. It is a maleate salt belonging to the tetracyclic antidepressant class. It contains dezocephalin (1+). It is a potent, non-competitive NMDA receptor antagonist (N-methyl-D-aspartate receptor) primarily used as a research tool. This drug was once considered for the treatment of various neurodegenerative diseases or diseases where NMDA receptors may play an important role. Due to its psychoactive effects, its application is mainly limited to animal and tissue experiments. Compound MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine maleate] is a potent anticonvulsant effective after oral administration, but its mechanism of action remains unclear. We detected a high-affinity binding site (Kd = 37.2 ± 2.7 nM) of [3H]MK-801 in the rat meninges. These binding sites exhibit thermal instability, stereoselectivity, and region specificity, with the highest density in the hippocampus, followed by the cerebral cortex, striatum, and medulla oblongata-pons. No binding was detected in the cerebellum. The MK-801 binding sites exhibit a novel pharmacological characteristic because none of the major neurotransmitter candidates bind to these sites. The only compounds that can compete with the [3H]MK-801 binding site are substances known to block excitatory amino acid responses mediated by N-methyl-D-aspartate (N-Me-D-Asp) receptor subtypes. These substances include the dissociative anesthetics phencyclidine and ketamine, and the sigmagenic opioid N-allyl normetazocine (SKF 10,047). In vitro neurophysiological studies using rat cortical sections showed that MK-801 has a potent, selective, and non-competitive antagonistic effect on the depolarization response of N-Me-D-Asp, but no such effect on erythrine or quisquilic acid. The potency of phencyclidine, ketamine, SKF 10,047 and MK-801 enantiomers as N-Me-D-Asp antagonists was closely correlated with their potency as [3H]MK-801 binding inhibitors (r = 0.99). This suggests that the binding site of MK-801 is associated with the N-Me-D-Asp receptor and provides an explanation for the mechanism of action of MK-801 as an anticonvulsant. [1]

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The effects of the anticonvulsant MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cycloheptene-5,10-imine maleate] on excitatory amino acid responses in cultured rat neocortical neurons were investigated using whole-cell and single-channel recording techniques. MK-801 gradually and persistently blocked N-methyl-D-aspartate (N-Me-D-Asp)-induced currents. However, during the inhibition of the N-Me-D-Asp response, the response to quisquiate or fucose was unaffected, suggesting that the N-Me-D-Asp receptor and the fucose/quisquiate receptor activate different groups of ion channels. The binding and dissociation of MK-801 appears to occur only when the N-Me-D-Asp-activated channels are in a neurotransmitter-activated state: MK-801 is only effective when administered concurrently with N-Me-D-Asp, and sustained exposure to N-Me-D-Asp accelerates the recovery from MK-801 blockade [time constant (τ) approximately 90 minutes at -70 to -80 mV]. Recovery from blockade during sustained N-Me-D-Asp administration is strongly voltage-dependent, with faster recovery at positive potentials (τ approximately 2 minutes at +30 mV). Mg2+ is thought to block N-Me-D-Asp-activated ion channels; at negative membrane potentials, MK-801 inhibits the blocking effect of Mg2+. In single-channel recordings with the patch-clamp facing outward, MK-801 significantly reduced N-Me-D-Asp-induced channel activity but did not significantly alter the major single-channel conductance. Consistent with open-channel blocking mechanisms, MK-801 reduced mean channel open time in a dose-dependent manner. [3] In summary, our study is the first to demonstrate that the same reactivation parameters and pharmacological agent (MK-801) can disrupt the reconsolidation of cocaine-related memories in a conditioned position preference (CPP) task but not in a self-dosing task. Furthermore, the reactivation parameters of the simulated self-dosing procedure itself (which should therefore promote the effective retrieval of cocaine-related memories) did not make the memory susceptible to MK-801 interference. Reducing the likelihood of persistent and unwanted memories by interfering with the memory reconsolidation process opens up an exciting new frontier for developing treatments for pathological conditions, including substance abuse. However, the complexities of memory storage and subsequent memory retrieval (which may ultimately lead to memory recoding) are only beginning to be elucidated, and further systematic studies on the timing and specific parameters of reactivation are needed. [5]

C16H15N

221.303

221.12

C, 86.84; H, 6.83; N, 6.33

77086-21-6

Dizocilpine maleate;77086-22-7;(-)-Dizocilpine maleate;121917-57-5

180081

White solid from cyclohexane

1.144±0.06 g/cm3

320.3±11.0 °C

68.75 ºC

3.479

1

1

0

17

313

2

C[C@]12C3=CC=CC=C3C[C@H](C4=CC=CC=C41)N2

LBOJYSIDWZQNJS-LYKKTTPLSA-N

InChI=1S/C16H15N/c1-16-13-8-4-2-6-11(13)10-15(17-16)12-7-3-5-9-14(12)16/h2-9,15,17H,10H2,1H3/t15?,16-/m0/s1

(5S)-5-methyl-10,11-dihydro-5H-5,10-epiminodibenzo[a,d][7]annulene

Dizocilpine; MK801; MK 801; MK-801; MK 801 Maleate; Dizocilpine [INN]; MK 801; Lopac-M-107; DIZOCILPINE; 77086-21-6; Dizocilpina; Dizocilpine [INN]; Dizocilpinum; MK-801; Dizocilpinum [INN-Latin]; Dizocilpina [INN-Spanish]; Lopac-M-108; MK-801 (Dizocilpine);

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)