Evaluation of brain pharmacokinetics of (+)MK-801 in relation to behaviour

Wegener, Nico; Nagel, Jens; Gross, Ralph; Chambon, Caroline; Greco, Sergio; Pietraszek, M.; Gravius, Andreas; Danysz, Wojciech

doi:10.1016/j.neulet.2011.08.012

Cited by 54 publications

(38 citation statements)

References 19 publications

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“…Similar results have been obtained in procedures that measure locomotor activity. For example, at doses used in this study, MK-801 significantly increases relatively low rates of locomotor activity in rats, whereas ketamine does not (Engin et al 2009; Gilmour et al 2009; Koike et al 2011; Réus et al 2011; Wegener et al 2011). …”

Section: Discussionmentioning

confidence: 65%

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

2014

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Rationale The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern. Objectives This study examined abuse-related effects of keta-mine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison. Methods Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency–rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2–10.0 mg/kg) and MK-801 (0.032–0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2–20.0 mg/kg/day) and acute cocaine (10.0 mg/kg). Results Following acute administration, ketamine (3.2–10 mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032–0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS. Conclusions The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.

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Section: Discussionmentioning

confidence: 65%

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

2014

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“…The much greater dose required for half-maximal suppression of 24-hour compared to one-hour mortality suggests that DZP, at least in a single-dose regimen, is less suited than MK-801 to ensuring extended survival after TMDT exposure. Current literature suggests that the pharmacokinetics of DZP and MK-801 are comparable in rodents (Vezzani et al, 1989, Walker et al, 1998, Musteata et al, 2008, Wegener et al, 2011). (Shakarjian et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Combined diazepam and MK-801 therapy provides synergistic protection from tetramethylenedisulfotetramine-induced tonic–clonic seizures and lethality in mice

et al. 2015

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The synthetic rodenticide, tetramethylenedisulfotetramine (TMDT), is a persistent and highly lethal GABA-gated Cl− channel blocker. TMDT is clandestinely produced, remains popular in mainland China, and causes numerous unintentional and deliberate poisonings worldwide. TMDT is odorless, tasteless, and easy to manufacture, features that make it a potential weapon of terrorism. There is no effective treatment. We previously characterized the effects of TMDT in C57BL/6 mice and surveyed efficacies of GABAergic and glutamatergic anticonvulsant treatments. At 0.4 mg/kg i.p., TMDT produced neurotoxic symptomatology consisting of twitches, clonic and tonic-clonic seizures, often progressing to status epilepticus and death. If administered immediately after the occurrence of the first clonic seizure, the benzodiazepine diazepam (DZP) effectively prevented all subsequent seizure symptoms, whereas the NMDA receptor antagonist dizocilpine (MK-801) primarily prevented tonic-clonic seizures. The latter agent, however, appeared to be more effective at preventing delayed death. The present study further explored these phenomena, and characterized the therapeutic actions of DZP and MK-801 as combinations. Joint treatment with both DZP and MK-801 displayed synergistic protection against tonic-clonic seizures and 24 hour lethality as determined by isobolographic analysis. Clonic seizures, however, remained poorly controlled. A modification of the treatment regimen, where DZP was followed 10 min later by MK-801, yielded a reduction in both types of seizures and improved overall outcome. Simultaneous monitoring of subjects via EEG and videography confirmed effectiveness of this sequential regimen. We conclude that TMDT blockage at GABAA receptors involves early activation of NMDA receptors, which contribute to persistent ictogenic activity. Our data predict that a sequential combination treatment with DZP followed by MK-801 will be superior to either individual therapy with, or simultaneous administration of, these two agents in treating TMDT poisoning.

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“…Data from rodent studies had shown that 50% occupancy of the NMDAR ion-channel by MK-801 could be obtained using a dose of 0.18 mg kg À1 [42,43]. In the present study, 0.6 mg kg À1 MK-801 was used, which is at least three times the in vivo EC 50 value and therefore should occupy the majority of NMDARs.…”

Section: Pre-treatment Studiesmentioning

confidence: 72%

Synthesis, radiolabeling and evaluation of novel amine guanidine derivatives as potential positron emission tomography tracers for the ion channel of the N-methyl-d-aspartate receptor

Klein

Chomet

Metaxas

et al. 2016

European Journal of Medicinal Chemistry

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Evaluation of brain pharmacokinetics of (+)MK-801 in relation to behaviour

Cited by 54 publications

References 19 publications

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

Combined diazepam and MK-801 therapy provides synergistic protection from tetramethylenedisulfotetramine-induced tonic–clonic seizures and lethality in mice

Synthesis, radiolabeling and evaluation of novel amine guanidine derivatives as potential positron emission tomography tracers for the ion channel of the N-methyl-d-aspartate receptor

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