dizocilpine-maleate and Fever

Pentylenetetrazole (PTZ) is one of the most valuable drugs used to induce seizure-like state in zebrafish especially considering the pharmacological screening for anticonvulsants and the study of basic mechanisms of epilepsy. Here, the effect of gender, weight and changes in temperature on latency to adult zebrafish reach classical seizure states induced by PTZ (10mM) was evaluated. Gender and weight (200-250mg versus 400-500mg) did not affect the profile of response to PTZ. When water temperature was changed from 22 to 30°C the lower temperature increased the latency time to reach seizure states and the higher temperature significantly decreased it, in comparison to the control group maintained at 26°C. The blockage of kainate receptors by DNQX (10μM) were unable to prevent the increased susceptibility of adult zebrafish exposed to hyperthermia and PTZ-induced seizures. The NMDA block by MK-801 (2.5μM) prevented the additive effect of hyperthermia on PTZ effects in adult zebrafish. This report emphasize that PTZ model in adult zebrafish exhibits no confounder factors from gender and weight, but water temperature is able to directly affect the response to PTZ, especially through a mechanism related to NMDA receptors.

Topics: Animals; Anticonvulsants; Body Weight; Convulsants; Dizocilpine Maleate; Female; Fever; Male; Models, Animal; Neurotransmitter Agents; Pentylenetetrazole; Seizures; Sex Characteristics; Temperature; Water; Zebrafish

Theophylline-associated convulsions are frequently exacerbated by fever, but the mechanisms behind it are still not completely understood. We investigated whether N-methyl-D-aspartic acid (NMDA) and gamma aminobutyric acid (GABA) receptors are involved in aminophylline (theophylline-2-ethylenediamine)-induced convulsions that are augmented by heat exposure-induced hyperthermia in mice. Mice exposed to 33 °C temperatures for 2 h had significantly increased body temperature (0.94 °C). Heat exposure significantly decreased time required for the onset of convulsions induced by an intraperitoneal (i.p.) injection of aminophylline (300 mg/kg). The shortened time for onset of convulsions was blocked by the NMDA receptor antagonist dizocilpine (0.1, 0.3 mg/kg, i.p.). However, the GABA(A) receptor agonist muscimol (1, 2 mg/kg, i.p.) did not have any effect. The pro-convulsant action of NMDA (100-125 mg/kg, i.p.) was enhanced by the heat exposure of 33 °C. However, the pro-convulsant actions of picrotoxin (3-4 mg/kg, i.p.), a GABA(A) receptor antagonist, were not affected by increased temperatures. These results suggest that NMDA receptors in the brain play a role in aminophylline-induced convulsions, which are augmented by heat exposure-induced hyperthermia in mice.

Topics: Aminophylline; Animals; Dizocilpine Maleate; Fever; Male; Mice; Muscimol; Seizures; Theophylline

The use of neuroprotective agents has been under investigation for the treatment of ischaemic brain stroke. In this study, we examined the effects of rosiglitazone and MK-801, two potential neuroprotectants, on thromboembloic focal stroke in hyperthermic rats. The animals were assigned into groups of rosiglitazone, MK-801 and control, all under both normothermic and hyperthermic conditions. A focal ischaemia was induced by injection of preformed clot into the origin of the middle cerebral artery. The animals were assessed by measuring infarct size and brain oedema and also evaluating neurological deficit and seizure activity. Rosiglitazone improved infarct volume and neurological deficit in both normo- (36%) and hyperthermic (63%) animals; but MK-801 only improved normothermic animals. Our results do not support the use of MK-801 in hyperthermic conditions of brain stroke but suggest that rosiglitazone may preserve its efficiency even in hyperthermia.

Topics: Animals; Brain Ischemia; Disease Models, Animal; Dizocilpine Maleate; Fever; Male; Neuroprotective Agents; Rats; Rats, Wistar; Rosiglitazone; Thiazolidinediones

Theophylline-associated convulsions have been observed most frequently in children with fever, but the mechanism is not fully understood. In this study, we investigated the basic mechanism of aminophylline [theophylline-2-ethylenediamine]-induced convulsions and the effects of Brewer's yeast-induced pyrexia in mice. Diazepam (5-10mg/kg, i.p.), a benzodiazepine receptor agonist, significantly prolonged the onset and significantly decreased the incidence of convulsions induced by aminophylline (350 mg/kg, i.p.). However, the gamma aminobutyric acid (GABA)A receptor agonist muscimol (1-4 mg/kg, i.p.), the GABAB receptor agonist baclofen (2-4 mg/kg, i.p.) and the N-methyl-D-aspartic acid receptor antagonist dizocilpine (0.1-0.3 mg/kg, i.p.) failed to protect against the convulsions. 20% Brewer's yeast (0.02 ml/g, s.c.) increased body temperature by 1.03, and also significantly shortened the onset and significantly increased the incidence of convulsions induced by aminophylline. The anticonvulsant action of diazepam (2.5-10mg/kg, i.p.) on the convulsions induced by aminophylline was reduced by Brewer's yeast-induced pyrexia. The proconvulsant actions of the GABAA receptor antagonists picrotoxin (3-4 mg/kg, i.p.) and pentylenetetrazol (40-60 mg/kg, i.p.) were enhanced by Brewer's yeast. These results suggest that the anticonvulsant action of diazepam against aminophylline is reduced by Brewer's yeast-induced pyrexia, and that GABAA receptors are involved in the aggravation of the convulsions by Brewer's yeast in mice.

Topics: Aminophylline; Animals; Anticonvulsants; Apnea; Bronchodilator Agents; Child; Convulsants; Diazepam; Dizocilpine Maleate; Fever; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; Humans; Infant; Japan; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Picrotoxin; Purinergic P1 Receptor Agonists; Saccharomyces cerevisiae; Seizures

The purpose of the current study was to explore the effects of N-methyl-D-aspartate (NMDA)-receptor antagonists (MK-801 and LY235959) administered intracerebroventricularly on the changes of both core temperature and hypothalamic levels of 2,3-dihydroxybenzoic acid (2,3-DHBA) induced by intracerebroventricular injection of glutamate (100 - 400 microg at 10 microl/rabbit) or intravenous administration of lipopolysaccharide (LPS) (2 microg/kg) in rabbits. The measurements of 2,3-DHBA were used as an index of the intrahypothalamic levels of hydroxyl radicals. The rise in both the core temperature and hypothalamic 2,3-DHBA could be induced by intracerebroventricular injection of glutamate or intravenous administration of LPS. The glutamate- or LPS-induced fever and increased hypothalamic levels of 2,3-DHBA were significantly antagonized by pretreatment with injection of MK-801 or LY235959 1 h before glutamate or LPS injection. The increased levels of prostaglandin E2 in the hypothalamus induced by glutamate or LPS could be suppressed by MK-801 or LY235959. The data demonstrate that prior antagonism of NMDA receptors in the brain, in addition to reducing prostaglandin E2 production in the hypothalamus, suppresses both the glutamate- and LPS-induced fever and increased hypothalamic hydroxyl radicals.

Topics: Animals; Dinoprostone; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fever; Glutamic Acid; Hydroxybenzoates; Hydroxyl Radical; Hypothalamus; Injections, Intraventricular; Isoquinolines; Lipopolysaccharides; Male; Rabbits; Random Allocation; Receptors, N-Methyl-D-Aspartate

The aim of this study was to investigate the effects of antioxidants (e.g. alpha-lipoic acid and N-acetyl-L-cysteine) as well as N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. MK-801 and LY235959) on the changes of both core temperature and hypothalamic levels of 2,3-dihydroxybenzoic acid (2,3-DHBA) induced by systemic administration of lipopolysaccharide (LPS) in rabbits. The measurements of 2,3-DHBA were used as an index of the intrahypothalamic levels of hydroxyl radicals. Intravenous administration of LPS (2-10 microg/kg) elicited a biphasic febrile response, with the core temperature maxima at 80 and 200 min post-injection. Each core temperature rise was accompanied by a distinct wave of cellular concentrations of 2,3-DHBA in the hypothalamus. The rise in both the core temperature and hypothalamic 2,3-DHBA could be induced by direct injection of glutamate (100-400 microg in 10 microl/rabbit) into the cerebroventricular fluid system. Either the early or the late phase of fever rise and increased hypothalamic levels of 2,3-DHBA following systemic injection of LPS were significantly antagonized by pretreatment with injection of alpha-lipoic acid (5-60 mg/kg, i.v.), N-acetyl-L-cysteine (2-20 mg/kg, i.v.), MK-801 (0.1-1 mg/kg, i.m.), or LY235959 (0.1-1 mg/kg, i.v.) 1 h before LPS injection. The increased levels of prostaglandin E(2) in the hypothalamus induced by LPS could be suppressed by alpha-lipoic acid or N-acetyl-L-cysteine pretreatment. These findings suggest that an NMDA receptor-dependent hydroxyl radical pathway in the hypothalamus of rabbit brain may mediate both the early and late phases of the fever induced by LPS.

Topics: Acetylcysteine; Analgesics, Non-Narcotic; Animals; Antioxidants; Body Temperature; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fever; Hydroxybenzoates; Hydroxyl Radical; Isoquinolines; Lipopolysaccharides; Male; Rabbits; Receptors, N-Methyl-D-Aspartate; Thioctic Acid

The present study shows that anoxic neuronal depolarization or NMDA receptor activation are potent stimuli for inducing spinal neuronal heat shock protein 70 (Hsp70). Spinal hyperthermia, despite its significant glutamate releasing effect, induced only glial Hsp70 upregulation. No significant increase in spinal Hsp70 expression after potassium depolarization was seen. Transient spinal ischemia (6 min) was induced by the inflation of a 2F Fogarty catheter placed into descending thoracic aorta during concurrent hypotension (40 mmHg). To determine the onset of anoxic depolarization extracellular concentration of K+ was measured in the lumbar dorsal horn using a microelectrode. Spinal hyperthermia (42 degrees C) or hypothermia (27 degrees C) was induced using a heat exchanger placed in the paravertebral subcutaneous space overlying Th5-S4 spinal segments. To measure extracellular concentration of glutamate during hyperthermia a loop dialysis catheter was implanted into lumbar intrathecal space. Receptor specific (NMDA, 3 microg) or non-specific (KCl, 10 microl, 1M) neuronal depolarization was induced using previously implanted intrathecal catheters. After ischemia, temperature manipulations or drug injections animals survived for 4 or 24h. Animals were then terminally anesthetized and perfusion fixed for Hsp70 immunohistochemistry. After spinal ischemia or NMDA administration a neuronal Hsp70 expression was seen at 24h. After spinal hyperthermia only glial expression was seen at 4h. Hyperthermia significantly increased CSF glutamate concentration, however, MK-801 (a non-competitive NMDA receptor antagonist) pretreatment failed to block Hsp70 expression. After hypothermia or potassium depolarization only minimal or no Hsp70 expression was seen in glial cells. Exposure of neuronal tissue to a specific stimuli may lead to intervals of increased resistance to subsequent neurotoxic/ischemic insult. The intervening biochemistry of this protection has been attributed to a family of molecules referred to as HSP. In the present study, we demonstrate that short-lasting anoxic depolarization or activation of NMDA receptor are the most potent stimuli for spinal neuronal Hsp70 induction. This effect corresponds with the observed ischemic tolerance state induced by short-lasting preconditioning spinal ischemia.

Topics: Amino Acids; Animals; Body Temperature; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fever; HSP70 Heat-Shock Proteins; Hypothermia; Immunohistochemistry; Injections, Spinal; Male; Microdialysis; N-Methylaspartate; Potassium; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Ischemia

Serotonin (5-HT) syndrome is the most serious side effect of antidepressants. Although several drugs have been used for the treatment of 5-HT syndrome, a universal pharmacotherapy has not been established. NMDA receptor antagonists have been reported to have neuroprotective effects. In the present study, the efficacy of NMDA antagonists, including memantine and MK-801, and potent 5-HT (2A) antagonists, including risperidone and ketanserin, was evaluated in a 5-HT syndrome animal model.. 5-Hydroxy-l-tryptophan (100 mg/kg) and clorgyline (2 mg/kg) were administered intraperitoneally in rats to induce 5-HT syndrome. The rectal temperature of the rats was measured, and the noradrenaline (NA) and 5-HT levels in the anterior hypothalamus were measured using a microdialysis technique.. In the group pretreated with saline, the rectal temperature increased to more than 40 degrees C, and all of the animals died within 90 min of the drug's administration. The NA and 5-HT levels in the anterior hypothalamus increased to about 15- and 1100-fold of the pre-administration levels, respectively. Pretreatment with risperidone (0.5 mg/kg) and ketanserin (5 mg/kg) prevented the development of hyperthermia and the increase in the NA level. Memantine (10 mg/kg) and MK-801 (0.5 mg/kg) also prevented the development of hyperthermia and the increase in the NA level. These results suggest that NMDA antagonists, as well as potent 5-HT (2A) antagonists, may be effective drugs for the treatment of 5-HT syndrome.. Since memantine is clinically well tolerated, this drug is a particularly promising therapeutic drug for 5-HT syndrome treatment.

Topics: 5-Hydroxytryptophan; Animals; Body Temperature; Clorgyline; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Excitatory Amino Acid Antagonists; Fever; Hypothalamus; Ketamine; Male; Memantine; Microdialysis; Norepinephrine; Rats; Rats, Wistar; Risperidone; Serotonin; Serotonin Antagonists; Serotonin Syndrome; Time Factors

Tolerance against ischemia can be induced in the CA1 region of the hippocampus of the brain. In gerbils tolerance evolvement is blocked by the NMDA-antagonist MK-801. To examine this mechanism in rats, MK-801 was administered i.p. 1 h prior to tolerance inducing ischemia. Body temperature and activity were monitored before and after ischemia, and show that MK-801 results in hyperthermia immediately after the injection, the post-ischemic body temperature remain elevated until 5 h post-ischemia in spite of the animals being less active than control animals. Histology shows that pre-treatment with MK-801 does not affect the CA1 neuronal density, and we thus conclude that for the used rat model, MK-801 does not affect development of ischemic tolerance.

Topics: Animals; Brain; Brain Ischemia; Dizocilpine Maleate; Fever; Male; Rats; Rats, Wistar

Permanent middle cerebral artery occlusion (MCAO) with the use of the suture technique causes hypothalamic damage with subsequent hyperthermia, which can confound neuroprotective drug studies. In the present study the neuroprotective effects of dizocilpine (MK-801) were compared in different permanent MCAO models with and without hypothalamic damage and hyperthermia.. Sixty Sprague-Dawley rats were treated with MK-801 or placebo, beginning 15 minutes before MCAO, and assigned to the following groups: suture MCAO (group I), macrosphere MCAO without hypothalamic damage (group II), or macrosphere MCAO with intentionally induced hypothalamic infarction (group III). Body temperature was measured at 3, 6, and 24 hours. Lesion size was determined after 24 hours (2,3,5-triphenyltetrazolium chloride staining).. Hypothalamic damage was present in animals in group I and was intentionally induced in group III with the use of a modified macrosphere MCAO technique. Body temperature was significantly increased 3, 6, and 24 hours after MCAO in these 2 groups of animals. Hypothalamic damage and subsequent hyperthermia could be avoided effectively by limiting the number of macrospheres (group II). MK-801 provided a highly significant neuroprotective effect in group II but not in groups I and III.. Hypothalamic damage with subsequent hyperthermia masked the neuroprotective effect of MK-801. This side effect can be avoided by using the macrosphere MCAO technique with a limited number of spheres. This model therefore may be more appropriate to study the effects of neuroprotective drugs in permanent focal cerebral ischemia than the suture method.

Topics: Animals; Body Temperature; Disease Models, Animal; Disease Progression; Dizocilpine Maleate; Fever; Hypothalamus; Infarction, Middle Cerebral Artery; Ligation; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; Titanium; Treatment Outcome

1. Administration of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to mice produces acute hyperthermia and long-term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine. 2. MDMA produced a dose-dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg(-1) (3 h apart) producing a 70% loss. 3. Pretreatment 30 min before each MDMA dose with either of the N-methyl-D-aspartate antagonists AR-R15896AR (20, 5, 5 mg kg(-1)) or MK-801 (0.5 mg kg(-1)x3) failed to provide neuroprotection. 4. Pretreatment with clomethiazole (50 mg kg(-1)x3) was similarly ineffective in protecting against MDMA-induced dopamine loss. 5. The free radical trapping compound PBN (150 mg kg(-1)x3) was neuroprotective, but it proved impossible to separate neuroprotection from a hypothermic effect on body temperature. 6. Pretreatment with the nitric oxide synthase (NOS) inhibitor 7-NI (50 mg kg(-1)x3) produced neuroprotection, but also significant hypothermia. Two other NOS inhibitors, S-methyl-L-thiocitrulline (10 mg kg(-1)x3) and AR-R17477AR (5 mg kg(-1)x3), provided significant neuroprotection and had little effect on MDMA-induced hyperthermia. 7. MDMA (20 mg kg(-1)) increased 2,3-dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR-R17477AR administration. Since AR-R17477AR was also found to have no radical trapping activity this result suggests that MDMA-induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissue-damaging peroxynitrites.

Topics: Animals; Chlormethiazole; Corpus Striatum; Cyclic N-Oxides; Dizocilpine Maleate; Dopamine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fever; Free Radicals; Hydroxybenzoates; Injections, Intraperitoneal; Male; Mice; Microdialysis; N-Methyl-3,4-methylenedioxyamphetamine; Nerve Degeneration; Neurons; Neuroprotective Agents; Nitric Oxide Synthase; Nitrogen Oxides; Pyridines; Salicylic Acid

1. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature (23 degrees C) produced a significant depletion of dopamine (DA) and its metabolites DOPAC and HVA in striatum at 24 and 72 hr, and 1 and 2 wk. 2. Three days post 4 x 10 mg/kg METH at 23 degrees C, an 80% decrease in striatal dopamine (DA) occurred, while the same dose at 4 degrees C produced only a 20% DA decrease, and 4 x 20 mg/kg METH at 4 degrees C produced a 54% DA decrease. A similar pattern in the decreases of the DA metabolites DOPAC and HVA was observed after METH administration. 3. At 23 degrees C (+)MK-801 completely blocked while phenobarbital (40% decrease) and diazepam (65% decrease) partially blocked decreases in striatal DA produced by 4 x 10 mg/kg METH. Decreases in DOPAC and HVA were similar to the decreases in DA after METH and antagonists. 4. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature also produced a significant depletion of serotonin (5-HT) in striatum at 24 and 72 hr, and 1 and 2 wk. The depletion of 5-HT metabolite 5-HIAA was found only at 72 hr post-dosing. 5. This depletion of 5-HT and its metabolite 5-HIAA at room temperature was blocked either by changing the environmental temperature to 4 degrees C, or by pretreatment with MK-801, diazepam and phenobarbital after METH treatment. 6. Therefore, these data suggest that drugs that block METH toxicity, such as haloperidol (D2 receptors), pentobarbital and phenobarbital (chloride channels) and MK-801 (NMDA/glutamate receptors), do not necessarily have the same mechanism of action but may either induce hypothermia or block induction of hyperthermia. 7. In summary, these studies show that in the mouse, environmental temperature greatly influences METH neurotoxicity, and that the protective effects of compounds such as diazepam, phenobarbital and MK-801 may be mediated by blockade of METH-induced hyperthermia.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Diazepam; Dizocilpine Maleate; Dopamine; Fever; Homovanillic Acid; Hydroxyindoleacetic Acid; Male; Methamphetamine; Phenobarbital; Rats; Serotonin; Temperature

Topics: Aging; Amphetamine; Animals; Arginine; Brain; Dizocilpine Maleate; Fever; Glutamic Acid; Haloperidol; Methamphetamine; Neurotoxins; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Receptors, N-Methyl-D-Aspartate; Stereoisomerism

The present study was inspired by two previous findings from the laboratory. The first was that dizocilpine maleate (MK-801) fails to reduce infarct size when the middle cerebral artery (MCA) is permanently occluded by an intraluminal filament technique in rats. In seeking the reasons for this we measured temperature and found that the body temperature of occluded animals increases to 39.0-39.5 degrees C during the first 2-3 h. In order to explore whether the rise in temperature was responsible for the lack of effect of MK-801, two groups of animals were studied, both containing animals which were subjected to 2 h of transient MCA occlusion and given MK-801 15 min before, as well as 6 and 24 h after ischemia. In one group, temperature was allowed to rise spontaneously during ischemia (39.0-39.5 degrees C). In the other, body temperature was maintained close to normal during ischemia, and for the first 6 h postischemically, by cooling of the ambient air. Infarct volume was assessed by triphenyltetrazolium chloride staining after 48 h of recovery. The results showed that MK-801 failed to reduce infarct size in animals whose body temperature rose during ischemia. In contrast, the drug markedly reduced infarct volume in temperature-controlled animals; in fact, 5/8 animals had no infarcts but selective neuronal damage only. The results suggest that amelioration of focal ischemic damage cannot be expected if body and brain temperature is allowed to rise above normal.

Topics: Animals; Body Temperature; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Fever; Male; Rats; Rats, Wistar

Hyperthermia-induced seizures (HS) in rats have been used as a model of febrile seizures. Activation of the N-methyl-D-aspartate (NMDA) receptor by increased extracellular glutamate (Glu) in the cortex during hyperthermia may be involved in the induction of HS and HS kindling. To confirm this hypothesis, the effects of a potent blocker of the NMDA receptor, MK-801, on the threshold and pattern of HS were evaluated. The threshold temperatures for rats given 0.1 (low dose) and 0.5 (high dose) mg/kg MK-801 (i.p.) for the first time were 41.6 degrees C (39.7-42) (median, range) and 42.0 (41.2-42.0), respectively, which were significantly higher than the 40.5 (39.4-41.2) for rats without MK-801 administration (P < 0.01). The recurrent occurrence of HS suppressed the increase in the threshold temperature with age, and changed the seizure from partial to generalized seizures (HS kindling), whereas these effects of recurrent HS on the threshold and pattern of HS were inhibited by the high dose (0.5 mg/kg) of MK-801. MK-801 blocks HS and HS kindling. The activation of the NMDA receptor during hyperthermia plays an important role in the induction of HS and HS kindling.

Topics: Age Factors; Animals; Dizocilpine Maleate; Fever; Glutamic Acid; Kindling, Neurologic; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

The effect of dizocilpine (MK-801), an N-methyl-D-aspartate receptor antagonist, on the development of tolerance to the analgesic and hyperthermic effects of morphine was determined in the rat. Tolerance to morphine in male Sprague-Dawley rats was induced by implanting subcutaneously 6 morphine pellets during a 7-day period. Two schedules of intraperitoneal injections of MK-801 were used. In one, the drug was injected once a day, and in the other it was injected twice a day. The doses of MK-801 were 0.03, 0.1 and 0.3 mg/kg. In the treatment once a day, MK-801 blocked the development of tolerance to the analgesic effect of morphine, but there was no dose-dependent effect. In the treatment twice a day, MK-801 produced a dose-dependent inhibition of tolerance to the analgesic effect of morphine. Higher doses of MK-801 produced high mortality. MK-801 given once a day or twice a day failed to affect the tolerance to the hyperthermic effect of morphine. In both schedules of MK-801 treatment, the highest dose of MK-801 resulted in high mortality. It is concluded that MK-801 is selective in blocking the tolerance to the analgesic effect of morphine in the rat.

Topics: Analgesia; Animals; Body Weight; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Tolerance; Fever; Male; Morphine; Rats; Rats, Sprague-Dawley

Stress-induced hyperthermia (SIH), which is seen in the last mice removed from the cage, is a novel animal model sensitive to anxiolytic drugs. SIH is antagonized by CL 218872 (25 and 50 mg/kg, os), by tracazolate (5 and 7.5 mg/kg, ip) and by 2-AP-5 (50 and 100 mg/kg, ip). At higher dose, CL 218872 (100 mg/kg, os) and tracazolate (12.5 mg/kg, ip) lose their activity. PK 9084 (5-40 mg/kg, ip) and CGS 9896 (2-20 mg/kg, both ip and os) were also ineffective in preventing SIH. The anti-hyperthermic effect of CL 218872 (25 mg/kg) and tracazolate (7.5 mg/kg) was blocked by the benzodiazepine antagonist Ro 15-1788 (15 mg/kg), CGS 9896 (10 mg/kg, os) also reversed the effect of CL 218872 (25 mg/kg) on SIH. Differently from anxiolytics, MK-801 (0.5-1 mg/kg, os), PCP (2.5 mg/kg, ip) and d-amphetamine (10 mg/kg, ip) evoked hyperthermia in the first set of mice and prevented a further stress-induced rise of body temperature in the last set of mice.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anti-Anxiety Agents; Body Temperature; Dextroamphetamine; Dizocilpine Maleate; Fever; Flumazenil; Male; Mice; Phencyclidine; Pyrazoles; Pyridazines; Quinolines; Receptors, GABA-A; Receptors, Serotonin; Single-Blind Method; Stress, Physiological

Experimental febrile seizures can be evoked in epileptic chicks by elevation of their body temperature. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists [(3-(+/- )2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), DL-2-amino-7-phosphosphonoheptanoic acid (APH), DL-2-amino-5-phosphonovaleric acid (APV), D-alpha-aminoadipic acid (AAA), and DL-alpha, epsilon-diaminopimelic acid (DAP)] and the noncompetitive NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5, 10-imine maleate (MK-801) produced dose-dependent increases in latency to the onset of seizures. Of the drugs tested, MK-801 had the highest potency followed in order by CPP = APH greater than APV much greater than AAA greater than DAP. There was a high correlation (r = 0.995) between the dose capable of doubling seizure latency and the affinity of the competitive NMDA antagonists for the NMDA receptor as determined by in vitro binding assays. These data suggest that NMDA receptor mediated mechanisms may be involved in the production of seizures in response to hyperthermia.

Topics: 2-Amino-5-phosphonovalerate; 2-Aminoadipic Acid; Amino Acids; Animals; Chickens; Diaminopimelic Acid; Dibenzocycloheptenes; Dizocilpine Maleate; Fever; Phenotype; Piperazines; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Synaptic Membranes