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1.
There is experimental evidence indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies, and ataxia). The present study was designed to investigate the efficacy of the nitric oxide (NO) donor molsidomine in counteracting these MK-801-induced behavioral effects in the rat. In a first study, post-training administration of molsidomine (at 4 but not 2 mg/kg) successfully antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, molsidomine (2 and 4 mg/kg) was shown to be unable to reverse MK-801-induced hypermotility but attenuated stereotypies (continuous movement whole cage, body sway, and head weaving) produced by MK-801. Moreover, at 4 mg/kg this NO donor counteracted MK-801-induced ataxia. Our findings indicate that molsidomine attenuates behavioral effects related to the hypofunction of the NMDA receptor suggesting that NO might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists. 相似文献
2.
Dai-Ying Zuo Yue Cao Lan Zhang Hai-Feng Wang Ying-Liang Wu 《Progress in neuro-psychopharmacology & biological psychiatry》2009
This study investigated the effects of acute and chronic administration of the non-competitive NMDA receptor antagonists MK-801 on c-Fos protein expression in different brain regions of mice with or without clozapine. MK-801 (0.6 mg/kg) acute administration produced a significant increase in the expression of c-Fos protein in the layers III–IV of posterior cingulate and retrosplenial (PC/RS) cortex, which was consistent with the previous reports. Moreover, we presented a new finding that MK-801 (0.6 mg/kg) chronic administration for 8 days produced a significant increase of c-Fos protein expression in the PC/RS cortex, prefrontal cortex (PFC) and hypothalamus of mice. Among that, c-Fos protein expression in the PC/RS cortex of mice was most significant. Compared to acute administration, we found that MK-801 chronic administration significantly increased the expression of c-Fos protein in the PC/RS cortex, PFC and hypothalamus. Furthermore, pretreatment of mice with clozapine significantly decreased the expression of c-Fos protein induced by MK-801 acute and chronic administration. These results suggest that c-Fos protein, the marker of neuronal activation, might play an important role in the chronic pathophysiological process of schizophrenic model induced by NMDA receptor antagonist. 相似文献
3.
MK-801 and ketamine induce heat shock protein HSP72 in injured neurons in posterior cingulate and retrosplenial cortex. 总被引:6,自引:0,他引:6
MK-801 and ketamine are noncompetitive N-methyl-D-aspartate (NMDA) receptor blockers that decrease brain injury in animal models of focal and global ischemia. Recent reports, however, suggested that MK-801 itself can damage neurons. Here we show that MK-801 (0.1 to 5.0 mg/kg) and ketamine (40 to 100 mg/kg) typically induce heat shock protein HSP72 mainly in layer 3 neurons of the posterior cingulate and retrosplenial cortex of the rat. These HSP72-immunoreactive neurons contain abnormal cytoplasmic vacuoles visualized by electron microscopy. The HSP72 immunoreactivity is maximal at 24 hours with 1.0-mg/kg doses of MK-801 and disappears by 2 weeks. Based on these data, we propose: (1) MK-801 and ketamine injure selected neurons, which express HSP72 in response to that injury. (2) Since HSP72 is induced for 1 to 2 weeks, the prolonged psychological side effects of MK-801, ketamine, phencyclidine, and related drugs could be related to this injury. (3) The neuroprotective effect of MK-801 is probably not related to HSP72 induction. (4) HSP72 immunocytochemistry is useful for studying nonlethal neuronal injury from a wide variety of brain insults. 相似文献
4.
Sex differences in the inhibitory effects of the NMDA antagonist, MK-801, on morphine and stress-induced analgesia 总被引:4,自引:0,他引:4
We examined the effects of intraperitoneal administrations of the noncompetitive NMDA receptor antagonist, (+) MK-801, its inactive enantiomer, (-) MK-801, and the prototypic opiate antagonist, naloxone, on restraint- and morphine-induced analgesia in male and female deer mice, Peromyscus maniculatus. Both restraint (30 min) and morphine (1.0 mg/kg) induced significant analgesic responses with male mice displaying significantly greater levels of opioid-induced analgesia than female animals. These analgesic responses were completely blocked by, naloxone (1.0 mg/kg), significantly reduced by (+) MK-801 (0.25 mg/kg) and unaffected by (-) MK-801 (0.25 mg/kg) pretreatments. There were significant male-female differences in the inhibitory effects of (+) MK-801; the higher levels of morphine- and restraint-induced analgesia of the males were completely blocked, while the lower level analgesic responses of the females were significantly reduced, but not blocked, by (+) MK-801. These observations provide further evidence that NMDA receptors are involved in the mediation of endogenous and exogenous opioid analgesia and show that there are significant male-female differences in the inhibitory effects of (+) MK-801 on opioid-mediated analgesia. 相似文献
5.
The selective 5-HT(6) receptor antagonist Ro 04-6790 attenuates psychotomimetic effects of the NMDA receptor antagonist MK-801 总被引:1,自引:0,他引:1
There are experimental evidences indicating that the non-competitive NMDA receptor antagonist MK-801 impairs cognition and produces a series of schizophrenia-like symptoms in rodents (hypermotility, stereotypies and ataxia). The present study was designed to investigate the efficacy of the selective 5-HT(6) receptor antagonist Ro 04-6790 in counteracting these MK-801-induced behavioural effects in the rat. The effects of Ro 04-6790 in antagonizing MK-801-induced memory deficits were assessed using the object recognition task. The ability of this 5-HT(6) receptor antagonist in counteracting hypermotility, stereotypies and ataxia produced by MK-801 were evaluated in a motor activity cage. Post-training administration of Ro 04-6790 (10 and to some extent also 3mg/kg) antagonized MK-801-induced performance deficits in a recognition memory test. In a subsequent study, Ro 04-6790 (3 and 10 mg/kg) reversed hypermotility and ataxia produced by MK-801. This 5-HT(6) receptor antagonist also alleviated MK-801-induced certain stereotypies. Our findings indicate that Ro 04-6790 attenuates behavioural effects related to the hypofunction of the NMDA receptor suggesting that this compound might be involved in the psychotomimetic effects of non-competitive NMDA receptor antagonists. 相似文献
6.
Global ischemia induces NMDA receptor-mediated c-fos expression in neurons resistant to injury in gerbil hippocampus. 总被引:7,自引:0,他引:7
The induction of c-fos protein-like immunoreactivity (CFPLI) was examined in the hippocampus of gerbils at several time points after transient global ischemia. c-Fos protein induction was largely confined to the dentate gyrus, CA3 and CA4 regions from 2 to 8 h after transient bilateral carotid occlusion. Little CFPLI was seen in the CA1 subfield, which is disproportionately sensitive to injury after global ischemia. c-Fos induction was completely blocked by pretreatment with MK-801 (3 mg/kg). Our results show that c-fos expression after global ischemia is NMDA receptor mediated, and mainly found in hippocampal neurons resistant to ischemic injury. 相似文献
7.
Expression of neurotrophins BDNF and NT-3, and their receptors in rat brain after administration of antipsychotic and psychotrophic agents 总被引:5,自引:0,他引:5
Lindén AM Väisänen J Lakso M Nawa H Wong G Castrén E 《Journal of molecular neuroscience : MN》2000,14(1-2):27-37
We have investigated the potential role of neurotrophic factors in antipsychotic drug action by examining the effects of antipsychotic
and psychotropic treatments on the mRNA expression of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and
their receptors, trkB and trkC, respectively, in rat brain. Neither acute nor chronic clozapine treatment significantly affected
the expression of these mRNAs in any brain area investigated, except for a decrease in trkB expression in the granule cells
of the olfactory bulb. We then examined the effects of the psychotropic agent MK-801. MK-801 (5 mg/kg; 4h) significantly increased
BDNF mRNA in the entorhinal cortex, but did not influence NT-3, trkB, or trkC expression in any brain area except for the
olfactory bulb. The induction of BDNF mRNA by MK-801 was attenuated by pre-treatment (1 h prior to MK-801 administration)
with the antipsychotics, clozapine (25 mg/kg) and haloperidol (2 mg/kg), but not with the antidepressant desipramine (15 mg/kg).
Finally, we confirmed that the effects of MK-801 on BDNF mRNA were reflected in the respective changes in BDNF protein levels:
MK-801 significantly increased anti-BDNF reactivity in the entorhinal cortex (126 ± 7% of control) while concomitantly decreasing
in the hippocampus (71 ± 2% of control). These data do not support the hypothesis that neurotrophins play an important role
in antipsychotic drug action, but rather suggest that induction of BDNF in the entorhinal cortex may play a significant role
in the psychotropic action of MK-801. 相似文献
8.
Małgorzata Pietraszek Jerzy Michaluk Irena Romańska Agnieszka Wąsik Krystyna Gołembiowska Lucyna Antkiewicz-Michaluk 《Neurotoxicity research》2009,16(4):390-407
1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous compound that is constantly present in the brain, and that exhibits neuroprotective activity. Our earlier study has suggested that 1MeTIQ may play a crucial physiological role in the mammalian brain as an endogenous regulator of dopaminergic activity. It is well known that central nervous system stimulants such as: amphetamine, cocaine, phencyclidine, and selective NMDA receptor antagonists, e.g., MK-801 produce neuropsychotoxicity (psychosis, addiction) that is indistinguishable from paranoid type schizophrenia. In rodents, phencyclidine and MK-801 are often used to evoke schizophrenia-like behavioral abnormalities which are inhibited by neuroleptics. The present study was designed to further investigate potential antipsychotic properties of 1MeTIQ by using both behavioral and neurochemical studies in the rat. We investigated the influence of 1MeTIQ (25 and 50 mg/kg ip) on locomotor hyperactivity, disruptions of prepulse inhibition (PPI), and working memory impairment induced by the NMDA receptor antagonist, MK-801 (0.2–0.3 mg/kg ip). In addition in the biochemical study, we analyzed the effect of 1MeTIQ on the changes in dopamine metabolism in different brain structures and in extraneuronal release of dopamine and glutamate in the rat frontal cortex, produced by MK-801. The concentration of dopamine (DA) and its metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA), as well as the extraneuronal concentration of dopamine and glutamate were established by HPLC. MK-801 (0.25 mg/kg ip) evoked significant disruptions of PPI and working memory impairment, and co-administration of 1MeTIQ at two investigated doses of 25 and 50 mg/kg ip did not antagonize these effects. On the other hand hyperactivity evoked by MK-801 as well as a rise in dopamine metabolism in specific brain structures and glutamate release in the frontal cortex was completely antagonized by pretreatment with 1MeTIQ. If the hyperlocomotion elicited by acutely administered MK-801 is a valid model of at least some aspects of schizophrenia, these results indicate that 1MeTIQ will show efficacy in treating this condition. In conclusions, the present study suggests that 1MeTIQ, an endogenous neuroprotective compound, exhibits also antipsychotic-like efficacy in some animal tests, and may be useful in clinical practice as a psychosis-attenuating drug in schizophrenic patients. However, 1MeTIQ did not attenuate sensorimotor gating deficit or working memory impairment evoked by MK-801 which may be served as a model of negative symptoms of schizophrenia. 相似文献
9.
This study examined the effect of GMP in two models of depression in mice. The immobility times in the forced swimming test (FST) and in the tail suspension test (TST) were significantly reduced by GMP (dose range: 5-50 mg/kg and 5-100 mg/kg, i.p., respectively), without accompanying changes in ambulation in an open-field. I.c.v. injection of GMP (320-480 nmol/site) also reduced the immobility in the FST without affecting ambulation. The immobility of mice treated with MK-801 (0.01 mg/kg) + GMP (50 mg/kg) was not significantly different from the result obtained with MK-801 or GMP alone, but GMP (or MK-801) + imipramine (15 mg/kg) treatment induced a stronger effect in FST than administration of either drug alone. Pretreatment with p-chlorophenylalanine (100 mg/kg, 4 days) completely blocked the anti-immobility effect of GMP, MK-801 or fluoxetine (32 mg/kg), but only partially that of imipramine in the FST. The results suggest that the antidepressant-like effects produced by the administration of GMP, like MK-801, may be due to an indirect serotonin activation resulting from blockade of NMDA receptors. 相似文献
10.
S. Tomitaka K. Hashimoto N. Narita A. Sakamoto Y. Minabe A. Tamura 《Brain research》1996,740(1-2):1-5
High-affinity N-methyl-d-aspartate (NMDA) receptor antagonists like MK-801 are known to induce the heat shock. protein, HSP70, in the posterior cingulate cortex and retrosplenial cortex of rat brain. Memantine, which is a low affinity uncompetitive NMDA receptor antagonist, has been used in the treatment of Parkinson's disease in Europe. The faster kinetics of memantine in blocking and unblocking the NMDA receptor-operated ion channel as opposed to high-affinity NMDA antagonists like MK-801 has been thought to account for the safety of memantine. The present study evaluated the neurotoxic potential of memantine and amantadine using the induction of HSP70 immunoreactivity in rat brain. Memantine (25, 50, 75 mg/kg) induced HSP70 in the posterior cingulate, retrosplenial cortex and dentate gyrus of rat brain. In contrast, amantadine (50, 100, 200 mg/kg) did not induce HSP70 in the rat brain. These results suggest that memantine has an antagonistic effect at NMDA receptor in vivo, and raises the possibility that high doses of memantine may cause neuronal damage similar to those observed with other high-affinity NMDA receptor antagonists. 相似文献
11.
12.
The effects of the specific N-methyl-D-aspartic acid (NMDA) receptor antagonist MK-801 (0.075 mg/kg), and the specific opiate receptor antagonist naloxone (10 mg/kg), on swim stress-induced analgesia (SSIA) were studied in opiate receptor-deficient (CXBK) and opiate receptor-rich (CXBH) mice. Animals were subjected to forced swimming, and analgesia was assessed using the hot-plate test. In CXBK mice SSIA was blocked by MK-801 but was completely insensitive to naloxone. In CXBH mice SSIA was partially attenuated both by naloxone and MK-801, and it was nearly abolished by a combination of these drugs. Morphine analgesia (10 mg/kg) was abolished by naloxone but completely unaffected by MK-801 in CXBH mice. These findings suggest that the NMDA receptor is critically involved in the non-opioid component of SSIA. 相似文献
13.
A M Snyder-Keller 《Experimental neurology》1991,113(2):155-165
Induction of the proto-oncogene c-fos occurred in cells of the striatum in response to stimuli that are known to release dopamine (DA). As revealed by fos immunocytochemistry, amphetamine (AMPH) produced c-fos induction in many cells of the medial two-thirds of the striatum of normal rats, with patchy labeling in the lateral third. The lateral patches were found to be coincident with patches of striatal neurons lacking calbindin immunoreactivity. In animals DA-depleted at birth, few fos-immunoreactive neurons were present in response to AMPH. In those with unilateral transplants of DA-rich mesencephalic tissue, c-fos induction was greater on the transplanted side. The DA D1 antagonist SCH 23390 completely blocked c-fos induction in all animals. The N-methyl-D-aspartate antagonist MK-801 also blocked c-fos induction by AMPH within the medial striatum, but intensified c-fos induction laterally in those animals with DA innervation. A second set of experiments examined the functional importance of c-fos induction in the AMPH sensitization of turning behavior that occurs in these animals. Both AMPH and stress produced turning, but only AMPH produced widespread c-fos induction, and stress-induced turning only occurred after exposure to AMPH. Treatment with MK-801 prior to AMPH administration blocked the subsequent development of stress-induced turning. Whereas a high dose of MK-801 (1.0 mg/kg) completely blocked c-fos induction, a lower dose (0.1 mg/kg) blocked c-fos induction in controls, but left patches of fos-immunoreactive neurons in lesioned animals given transplants. Thus the sensitization of transplant-related behaviors is NMDA dependent and associated with c-fos induction in host striatal neurons. 相似文献
14.
Eriksson C Zou LP Ahlenius S Winblad B Schultzberg M 《Brain research. Molecular brain research》2000,85(1-2):103-113
The cytokines interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1ra) are rapidly induced in response to excitotoxic and ischemic brain damage. The aim of the present study was to investigate the influence of a non-competitive (dizocilpine maleate, MK-801) and a competitive ((R)-CPP) NMDA receptor antagonist on the transient cytokine expression in the rat brain induced by systemic kainic acid administration. Peripheral administration of kainic acid (10 mg/kg, i.p.) results in a transient expression of IL-1 beta and IL-1ra mRNA, mainly in microglia, in regions showing neurodegeneration such as the hippocampus, thalamus, amygdala, and certain cortical regions. In addition, a few neurons expressing IL-1ra mRNA were observed in the piriform cortex and amygdala following kainic acid injection. Administration of MK-801 (i.p.) 1 h prior to kainic acid injection reduced cytokine expression in all of these regions. MK-801 at 3.0 mg/kg decreased the IL-1 beta mRNA expression, blocked or decreased the IL-1ra mRNA expression, depending on the brain region. MK-801 at 5.0 mg/kg abolished IL-1ra mRNA expression in all of the regions, whereas the IL-1 beta mRNA expression was decreased or blocked, depending on the brain region, or the time point investigated. Peripheral administration of (R)-CPP (15 mg/kg, i.p.) 15 min prior to the kainic acid injection abolished the IL-1 beta mRNA expression. The IL-1ra mRNA expression was abolished in all regions except for a few neurons in the piriform cortex. The finding that NMDA receptor antagonists inhibit the IL-1 beta and IL-1ra mRNA synthesis induced by kainic acid suggests that NMDA receptor activation may be involved in triggering cytokine synthesis following excitotoxic brain damage. 相似文献
15.
The N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 has been shown to induce an acute Fos and Fos-related antigen (Fra) expression in the rat retrosplenial granular cortex (RSG), but the exact composition of the Fos protein family and their individual dynamic alterations are unknown. We examined this issue using immunocytochemistry and Western blot analysis with two antibodies that recognize, respectively, Fos and all the identified members of Fos protein family. Immunocytochemistry detected a rapid and transient expression of Fos proteins in some RSG neurons and a delayed and prolonged expression of Fra proteins in most RSG neurons following a single systemic MK-801 injection (1 mg/kg). Multiple MK-801 injections (i.e., ten consecutive injections once every other day; 1 mg/kg) produced a moderate Fra expression but failed to induce detectable Fos expression. Western blot analysis further showed a transient expression of 72-kDa Fos proteins following a single MK-801 injection and a prolonged expression of 46- and 43-kDa Fra proteins after either a single or multiple MK-801 administration. The delayed onset and prolonged expression of these Fra proteins suggest that they may be DeltaFosB. The possible relevance of these results to clinical psychotomimetic effects of the NMDA receptor antagonists phencyclidine and ketamine is discussed. 相似文献
16.
The impairment of rotarod ability and the convulsive activity of phencyclidine (PCP) and MK-801 were compared in male CD-1 mice. The putative interaction between nifedipine and PCP and MK-801 on these behavioral measurements was also quantitated and compared. MK-801 produced a dose dependent inhibition of rotarod ability with an ED50 of 0.5 mg/kg. Nifedipine potentiated the impairment of rotarod ability by MK-801. Both PCP and MK-801 produced convulsive behavior in mice which was characterized by jumping and wild running fits; the CD50 for MK-801 was 1.3 mg/kg. Nifedipine dose dependently inhibited the convulsions associated with MK-801 and PCP. PCP but not MK-801 increased [3H]nitrendipine binding to dihydropyridine (DHP) binding sites on mouse brain membranes. MK-801 blocked the effects of PCP on [3H]nitrendipine binding. These findings suggest that MK-801 is a potent PCP-like drug which interacts with nifedipine and neuronal DHP binding sites. Nifedipine's reduction of the hyperactivity and convulsions elicited by MK-801 may be of importance in the eventual development of MK-801 as an antiischaemic and anticonvulsant drug. 相似文献
17.
MK-801, a novel anticonvulsant which is a potent N-methyl-d-aspartate antagonist, attenuated or blocked seizures and convulsions induced by the irreversible organophosphorus anticholinesterase inhibitor soman. Guinea pigs chronically instrumented for electrocorticogram recording were given a low dose (1 mg/kg) or a high dose (5 mg/kg) of MK-801 or saline vehicle 30 min prior to receiving 2 x LD50 of soman. All animals were treated with atropine methylnitrate and pralidoxime chloride 30 sec after soman injection. All saline control subjects exhibited severe seizures and convulsions shortly after receiving soman. Low dose MK-801 greatly attenuated and high dose MK-801 completely blocked seizure activity. Animals treated with MK-801 recovered faster and had a much greater probability of survival for 48 hr after soman exposure than did controls. This is the first demonstration of the involvement of the excitatory amino acid neurotransmitter system in seizures and convulsions induced by a cholinesterase inhibitor. 相似文献
18.
The electrophysiological effects of the non-competitive
(NMDA) antagonist (+)-MK801 (MK-801) on nigrostriatal and mesoaccumbal dopaminergic (DA) neurons were evaluated in chloral hydrate-anesthetized rats. MK-801 (0.05–3.2 mg/kg, i.v.) stimulated the firing rates of 14 (74%) of 19 nigrostriatal DA (NSDA) neurons and all 16 mesoaccumbal DA (MADA) neurons tested. Stimulatory effects of the drug were more prominent on MADA neurons. Interspike interval analysis revealed that MK-801 also regularized DA neuronal firing pattern. Acute brain hemitransection between the midbrain and forebrain attenuated the stimulatory effects of MK-801 on firing rate and blocked the effects on firing pattern. Similar to MK-801, hemitransection itself increased NSDA and MADA cell firing rates and regularized firing pattern. Both i.v. and iontophoretic MK-801 blocked the excitatory effects of iontophoretic NMDA but did not effect excitations caused by the non-NMDA glutamatergic receptor agonists quisqualate and kainate. Iontophoretic MK-801 had no effect alone. These results suggest that the excitatory effects of i.v. MK-801 on DA neuronal activity are not due to direct actions on DA neurons. Glutamatergic projections originating anterior to the hemistransection appear to play a role in the effectrs of MK-801 on DA neuronal activity. 相似文献
19.
Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. 总被引:27,自引:0,他引:27
J M Gidday A R Shah R G Maceren Q Wang D A Pelligrino D M Holtzman T S Park 《Journal of cerebral blood flow and metabolism》1999,19(3):331-340
Neuroprotection against cerebral ischemia can be realized if the brain is preconditioned by previous exposure to a brief period of sublethal ischemia. The present study was undertaken to test the hypothesis that nitric oxide (NO) produced from the neuronal isoform of NO synthase (NOS) serves as a necessary signal for establishing an ischemia-tolerant state in brain. A newborn rat model of hypoxic preconditioning was used, wherein exposure to sublethal hypoxia (8% oxygen) for 3 hours renders postnatal day (PND) 6 animals completely resistant to a cerebral hypoxic-ischemic insult imposed 24 hours later. Postnatal day 6 animals were treated 0.5 hour before preconditioning hypoxia with the nonselective NOS inhibitor L-nitroarginine (2 mg/kg intraperitoneally). This treatment, which resulted in a 67 to 81% inhibition of calcium-dependent constitutive NOS activity 0.5 to 3.5 hours after its administration, completely blocked preconditioning-induced protection. However, administration of the neuronal NOS inhibitor 7-nitroindazole (40 mg/kg intraperitoneally) before preconditioning hypoxia, which decreased constitutive brain NOS activity by 58 to 81%, was without effect on preconditioning-induced cerebroprotection, as was pretreatment with the inducible NOS inhibitor aminoguanidine (400 mg/kg intraperitoneally). The protective effects of preconditioning were also not blocked by treating animals with competitive [3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate; 5 mg/kg intraperitoneally] or noncompetitive (MK-801; 1 mg/kg intraperitoneally) N-methyl-D-aspartate receptor antagonists prior to preconditioning hypoxia. These findings indicate that NO production and activity are critical to the induction of ischemic tolerance in this model. However, the results argue against the involvement of the neuronal NOS isoform, activated secondary to a hypoxia-induced stimulation of N-methyl-D-aspartate receptors, and against the involvement of the inducible NOS isoform, but rather suggest that NO produced by the endothelial NOS isoform is required to mediate this profound protective effect. 相似文献
20.
Sanjay N. Thorat Marc J. Barjavel George A. Matwyshyn Hemendra N. Bhargava 《Brain research》1994,642(1-2)
The effects of NG-monomethyl-l-arginine (l-NMMA), an inhibitor of nitric oxide (NO) synthase and MK-801, an NMDA receptor antagonist on abrupt and naltrexone-precipitated abstinence symptoms were determined in male Swiss-Webster mice rendered dependent on morphine by subcutaneous implantation of a pellet containing 75 mg of morphine base for 3 days. Mice which served as controls were implanted with placebo pellets. Six hours after pellet removal, mice were injected intraperitoneally with either the vehicle or MK-801 (0.03, 0.1 and 0.3 mg/kg). Thirty minutes later the animals were injected with naltrexone subcutaneously (50 μg/kg) and the intensity of abstinence symptoms were determined. Of the three doses of MK-801 used, only 0.1 mg/kg dose inhibited the jumping behavior precipitated by naltrexone in morphine-dependent mice. Whereas the lower dose (0.03 mg/kg) of MK-801 increased, the higher doses of MK-801 (0.1 and 0.3 mg/kg) displayed a decrease in the formation of fecal boli. Administration of MK-801 did not affect the body weight loss observed during abrupt withdrawal (induced by removal of the pellets) in morphine-dependent mice. MK-801 at 0.1 mg/kg dose further decreased the body temperature during abrupt withdrawal in morphine-dependent mice. Other two doses of MK-801 (0.03 and 0.3 mg/kg) did not modify the hypothermia observed during abrupt morphine withdrawal. On the other hand, l-NMMA (0.02 to 4.0 mg/kg) injected intraperitoneally 15 min prior to the naltrexone administration blocked the stereotyped jumping response in a dose-dependent manner. Higher doses of l-NMMA 2.0 and 4.0 mg/kg also decreased the number of fecal boli formation. l-NMMA (0.2 to 4.0 mg/kg) also significantly reduced the abrupt withdrawal-induced body weight loss in morphine-dependent mice. Thus MK-801 has very little effect, which is not dose-dependent, on abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. However, the l-NMMA has more profound dose-dependent effects on both the abrupt and antagonist-precipitated withdrawal in morphine-dependent mice. It is concluded that the inhibitors of NO synthase may be more beneficial than NMDA receptor antagonists in managing the symptoms of morphine abstinence syndrome. 相似文献