Anticonflict effect of MK-801 in rats: Time course and chronic treatment studies

1. We have used young pigs, each prepared surgically with a Thiry-Vella loop of proximal small intestine, to study the time course of changes in the intestinal absorption of calcium, phosphate, sodium, glucose and water and on the plasma levels of 1,25-dihydroxyvitamin D after treatment of the animals with glucocorticoids. 2. Perfusion of the intestinal loop for 6 h with a solution containing hydrocortisone or betamethasone was without effect on the absorption of calcium or phosphate. 3. The oral administration of betamethasone stimulated the absorption of calcium and phosphate by 15–20% for 2–3 days before the trend was reversed and absorption was progressively reduced. 4. Chronic treatment with betamethasone inhibited only the active component of calcium and phosphate absorption. 5. Treatment with betamethasone was associated with a sustained 25–50% increase, to a maximum by 2 days, in the absorption of sodium, glucose and water. 6. Plasma levels of 1,25-dihydroxyvitamin D were reduced within 2 days of the start of treatment and reached a minimum (40–50% decrease) in 4–6 days. 7. We conclude that the initial stimulation of calcium and phosphate absorption is caused by the increased absorption of water. The long-term decrease in absorption may not be caused solely by the decreased circulating levels of 1,25-dihydroxyvitamin D since absorption continued to fall for several weeks after 1,25-dihydroxyvitamin D levels had reached a minimum.

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NREM delta stimulation following MK-801 is a response of sleep systems

Journal of Neurophysiology ◽

10.1152/jn.1996.76.6.3714 ◽

1996 ◽

Vol 76 (6) ◽

pp. 3714-3720 ◽

Cited By ~ 27

Author(s):

I. G. Campbell ◽

I. Feinberg

Keyword(s):

Sleep Deprivation ◽

Eye Movement ◽

Time Course ◽

Sleep Onset ◽

Nrem Sleep ◽

Rapid Eye Movement ◽

Mk 801 ◽

Regulatory Systems ◽

Sleep Centers ◽

Electroencephalogram Eeg

1. We have previously shown that noncompetitive blockade of the N-methyl-D-aspartate (NMDA)-gated cation channel with ketamine or Dizocilpine maleate (MK-801) increases the intensity of non-rapid-eye-movement (NREM) delta during subsequent sleep. This delta increase [measured as integrated amplitude (IA) in 1- to 4-Hz electroencephalogram (EEG)] occurs in the 12-h period following intraperitoneal injection. However, the 12 h after drug injection is also the period in which these drugs induce neurotoxic changes, raising the possibility that the increased delta represents toxic EEG slowing rather than an increase in the physiological delta waves of NREM sleep. 2. We hypothesized that the time course of delta stimulation could be separated from the time course of neurotoxicity. We tested this hypothesis by injecting 0.3 mg/kg MK-801 at the start of the dark period (DP) and depriving rats of sleep until the onset of the light period (LP) 12 h later. 3. There were two control groups: one received MK-801 at the start of the DP with no further manipulation, and the second received a saline injection at DP onset followed by 12 h of sleep deprivation. The dependent variable was the amount of delta IA in the LP, whose onset was 12 h after MK-801 injection. Total IA in the LP was significantly greater in rats that received MK-801 followed by sleep deprivation than in rats that received sleep deprivation alone or MK-801 alone. 4. This finding indicates that delta stimulation by MK-801 is maintained over 12 h of waking, indicating that the delta increase is not due to toxic EEG slowing or persisting MK-801. Instead, NMDA channel blockade by MK-801 increases the homeostatic need for delta or else directly alters sleep regulatory systems. We speculate that these effects are mediated by hypothalamic sleep centers through control of neuroendocrine pulses that produce both NREM and rapid-eye-movement sleep. 5. Imposing a period of waking between drug administration and sleep onset may prove a generally useful strategy for determining whether a drug affects the homeostatic need for sleep or acutely stimulates sleep systems. This strategy can also help distinguish between toxic and physiological increases in delta EEG.

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Effect of chronic treatment with dizocilpine (MK-801) on the behavioral response to dopamine receptor agonists in the rat

Psychopharmacology ◽

10.1007/bf02245275 ◽

1992 ◽

Vol 107 (4) ◽

pp. 591-594 ◽

Cited By ~ 47

Author(s):

Rossella Dall'Olio ◽

Ottavio Gandolfi ◽

Nicola Montanaro

Keyword(s):

Dopamine Receptor ◽

Behavioral Response ◽

Chronic Treatment ◽

Mk 801 ◽

Dopamine Receptor Agonists ◽

Receptor Agonists

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The nature and time course of neuronal vacuolation induced by the N-methyl-d-aspartate antagonist MK-801

Acta Neuropathologica ◽

10.1007/s004010050050 ◽

1994 ◽

Vol 87 (1) ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

R. N. Auer ◽

K. C. Coulter

Keyword(s):

Time Course ◽

Mk 801 ◽

Neuronal Vacuolation

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Characterization of the Anticonflict Effect of MK-801, a Non-Competitive NMDA Antagonist

Pharmacology & Toxicology ◽

10.1111/j.1600-0773.1995.tb00116.x ◽

1995 ◽

Vol 76 (2) ◽

pp. 122-127 ◽

Cited By ~ 9

Author(s):

A. K. Söderpalm ◽

O. Blomqvist ◽

J. A. Engei ◽

B. Söderpalm

Keyword(s):

Nmda Antagonist ◽

Mk 801 ◽

Anticonflict Effect

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MK-801 does not prevent impaired cerebrovascular reactivity to CO2 during hypoglycemia in piglets

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.6.h2124 ◽

1993 ◽

Vol 264 (6) ◽

pp. H2124-H2130

Author(s):

P. J. St Jacques ◽

J. R. Kirsch ◽

M. N. Diringer ◽

R. J. Traystman

Keyword(s):

Nmda Receptor ◽

Time Course ◽

Nmda Receptor Antagonist ◽

Cerebrovascular Reactivity ◽

Co2 Reactivity ◽

Resistance Change ◽

Mk 801 ◽

Cerebrovascular Resistance ◽

Cerebrovascular Co2 Reactivity ◽

Made In

We tested the hypothesis that severe insulin-induced hypoglycemia would depress cerebrovascular reactivity to CO2 via a mechanism that could be prevented by administration of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in infant piglets. Cerebral blood flow (CBF) was measured (microspheres) in 2- to 3-wk-old pentobarbital-anesthetized piglets during hypocapnia, normocapnia, and hypercapnia. Repeat CBF measurements were made either 1 (n = 5) or 2 h (n = 6) after insulin (200 U/kg iv) to elicit the time course of altered reactivity to CO2. Repeat CBF measurements were made in a third group (n = 5) 2 h after treatment with insulin and MK-801 (1.5 mg/kg iv bolus, 0.15 mg.kg-1.h-1 iv infusion) to determine whether any alteration in reactivity to CO2 was due to a mechanism involving the NMDA receptor. Cerebrovascular resistance and cerebral O2 consumption (CMRO2) were calculated with each measurement of CBF. Cerebrovascular response to CO2 (change in cerebrovascular resistance/change in arterial CO2 tension) was ablated in the group of piglets exposed to 1 or 2 h of hypoglycemia (preinsulin 1-h group, 0.038 +/- 0.007; preinsulin 2-h group, 0.023 +/- 0.004 mmHg.ml-1.min.100 g.mmHg CO2(-1)). Treatment with MK-801 did not alter normoglycemic CO2 reactivity (preinsulin, 0.032 +/- 0.005 mmHg.ml-1.min.100 g.mmHg CO2(-1)) and did not prevent ablation of cerebrovascular CO2 reactivity during hypoglycemia. CMRO2 was not affected by hypoglycemia in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

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MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.153 ◽

2015 ◽

Vol 35 (12) ◽

pp. 1903-1909 ◽

Cited By ~ 14

Author(s):

Vincent Prinz ◽

Anna-Maria Hetzer ◽

Susanne Müller ◽

Mustafa Balkaya ◽

Christoph Leithner ◽

...

Keyword(s):

Time Course ◽

Time Window ◽

Neuronal Degeneration ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Cell Loss ◽

Ischemic Lesion ◽

Mk 801 ◽

Delayed Treatment ◽

Secondary Time

Cerebral ischemia in the territory of the middle cerebral artery (MCA) can induce delayed neuronal cell death in the ipsilateral substantia nigra (SN) remote from the primary ischemic lesion. This exofocal postischemic neuronal degeneration (EPND) may worsen stroke outcomes. However, the mechanisms leading to EPND are poorly understood. Here, we studied the time course of EPND via sequential magnetic resonance imaging (MRI) and immunohistochemistry for up to 28 days after 30 minutes occlusion of the MCA (MCAo) and reperfusion in the mouse. Furthermore, the effects of delayed treatment with FK506 and MK-801 on the development of EPND were investigated. Secondary neuronal degeneration in the SN occurred within the first week after MCAo and was characterized by a marked neuronal cell loss on histology. Sequential neuroimaging examinations revealed transient MRI changes, which were detectable as early as day 4 after MCAo and thus heralding histologic evidence of EPND. Treatment with MK-801, an established anti-excitotoxic agent, conferred protection against EPND even when initiated days after the initial ischemic event, which was not evident with FK506. Our findings define a secondary time window for delayed neuroprotection after stroke, which may provide a promising target for the development of novel therapies.

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