Low Dose Of MK-801 Research Articles

Long-term effects of neonatal MK-801 treatment on prepulse inhibition in young adult rats

Blockade of N-methyl-D-asparate (NMDA) receptors has been shown to produce some of the abnormal behaviors related to symptoms of schizophrenia in rodents and human. Neonatal treatment of rats with non-competitive NMDA antagonists has been shown to induce behavioral abnormality in a later period. The aim of this study was to determine whether brief disruption of NMDA receptor function during a critical stage of development is sufficient to produce sensorimotor-gating deficits in the late adolescence or early adulthood in the rat. Male pups received the NMDA receptor blocker MK-801 (0.13 or 0.20 mg/kg), or an equal volume of saline on postnatal day (PD) 7 through 10. The animals were tested twice for prepulse inhibition (PPI) and locomotor activity in pre- (PD 35-38) and post- (PD 56-59) puberty. Neonatal exposure to both doses MK-801 disrupted PPI in the adolescence and early adulthood. Low-dose MK-801 elicited long-term effects on startle amplitudes, whereas high-dose MK-801 did not. Neither dose of MK-801 showed a significant effect on spontaneous locomotor activity, whereas the high dose attenuated rearing. The results of this study suggest neonatal exposure to MK-801 disrupted sensorimotor gating in the adolescence and early adulthood stages. These findings indicate that rats transiently exposed to NMDA blockers in neonatal periods are useful for the study of the pathophysiology and treatment of schizophrenia.

Low dose MK-801 reduces social investigation in mice

To characterize MK-801's effect on social behavior in mice, we examined adult male ICR mice for interaction with companion mice (juvenile male). Test mice were injected with either saline or MK-801 (0.1 mg/kg), and were tested 30 min later for their social behavior during a 5-min session. A second encounter took place 30 min later, with either a familiar companion mouse (the same as in the initial encounter) or a novel mouse. In saline controls, second encounter with a familiar companion mouse showed reduced social investigative behaviors (anogenital sniffing and staying together), indicating habituation toward a familiar mouse. Second encounter with a novel companion mouse did not show habituation in social investigative behaviors. Pretreatment with MK-801 reduced anogenital sniffing during the first encounter. At the second encounter, these mice displayed non-discriminative habituation of social investigative behaviors, with reduced anogenital sniffing and staying together, regardless of whether the companion mouse was a familiar or a novel one. These results indicate that MK-801 affected exploratory activities of mice, resulting in both reduced social investigative behaviors during first encounter with a companion mouse, and diminished discriminative capacities for a familiar vs. a novel companion mouse during subsequent encounter.

P.3.b.001 Restoration of latent inhibition in ovariectomized rats by neuroleptics requires estrogen

The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801–induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. Published by Elsevier Science Inc., 2000

Two-methyl-6-phenylethynyl-pyridine (MPEP), a metabotropic glutamate receptor 5 antagonist, with low doses of MK801 and diazepam: A novel approach for controlling status epilepticus

By intravenous administration of group I metabotropic glutamate receptor antagonists at 1 or 2 h during pilocarpine induced status epilepticus (PISE), we showed that mGluR1 antagonists AIDA or LY367385 (at dosages ranging from 25 to 200 mg/kg), mGluR5 antagonists SIB1757 (at dosages ranging from 25 to 200 mg/kg), SIB1893 (from 25 to 100 mg/kg), MPEP (from 25 to 100 mg/kg) injected at 1 or 2 h during PISE were ineffective in controlling status epilepticus (SE). However, when administered at 1 h during PISE, MPEP at 200 mg/kg, combination of MPEP (200 mg/kg) with MK801 (0.1 mg/kg) or with MK801 (0.1 mg/kg) and diazepam (0.5 mg/kg), combination of SIB1893 (200 mg/kg) with MK801 (0.1 mg/kg) could effectively control behavioral SE, and were neuroprotective. In particular, the combination of MPEP with MK801 and diazepam could stop both behavioral SE and electrical SE (under EEG monitoring) within a few minutes after the administration. HPLC study showed that a high level of MPEP was maintained in the blood and its metabolism rate was slow in experimental mice with PISE. We therefore concluded that the combination of MPEP (200 mg/kg) with MK801 (0.1 mg/kg) and diazepam (0.5 mg/kg) could effectively stop SE and its subsequent neuronal loss in the hippocampus when administered 1 h during PISE. It may provide a new approach to effectively control intractable SE.

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic place avoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for four daily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitive deficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWM compared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higher doses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks. Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar rats can efficiently solve both spatial tasks; however, they are more sensitive to MK-801-induced behavioural deficit. This has relevance for modeling of the schizophrenia-related deficits and for screening substances for their therapeutic potential.

Paradoxical effects of very low dose MK-801

Systemic injection of the noncompetitive NMDA ( N-methyl- d-aspartate) receptor antagonist MK-801 (dizocilpine maleate) is known to cause increased locomotion and various stereotypic behaviors in rodents. However, the MK-801 dose ranges commonly examined usually begin at tenth of mg/kg and going higher, with the implicit assumption of lower doses being ineffective. We report here that very low dose MK-801, well below the commonly studied doses, exert distinct effects on rodent behaviors. In C57BL/6 mice, very low dose MK-801 (0.02 mg/kg) has strikingly different effects than higher doses commonly reported in the literature. Locomotion, rearing, grooming, and other behaviors are strongly inhibited, replaced by periods of immobility. This is in contrast to the mobility-enhancing effect of MK-801 at commonly reported dose ranges. The effects of very low dose MK-801 are qualitatively similar to those observed with moderate doses (0.1–0.2 mg/kg) of the typical antipsychotic haloperidol. These results highlight the complexity of the dose–response relation for MK-801-induced behaviors.

The NMDA-receptor antagonist MK-801 selectively disrupts reversal learning in rats

We tested the hypothesis that inhibition of NMDA-receptors in rats would lead to a selective impairment of reversal learning in a serial reversal task in the Skinner box. Low doses of MK-801 (0.025 and 0.05 mg/kg) did not affect acquisition of the two-lever discrimination, but impaired performance during the first reversal more than during the third reversal. Similar effects were observed during the series of extinction sessions. The high dose (0.1 mg/kg) completely inhibited reversal and extinction learning, as the rats perseverated in pressing the previously rewarded lever(s). We conclude that NMDA receptor blockade leads to a selective impairment in cognitive flexibility, and shows some similarity to transient inactivation of the medial prefrontal cortex in this respect.

Chronic neonatal N-methyl- d-aspartate receptor blockade induces learning deficits and transient hypoactivity in young rats

A blockade of N-methyl- d-aspartate (NMDA)-type of glutamate receptor in rodents is believed to provide a pharmacological model of schizophrenia-related psychosis. Since neurodevelopmental abnormality, at least partly, could contribute to the pathogenesis of schizophrenia, the aim of this study was to recapitulate cognitive impairments accompanying this disorder in rats by a chronic neonatal treatment with a noncompetitive NMDA antagonist MK-801. Rat pups were treated with a low dose of MK-801 (0.05 mg/kg sc) chronically from early postnatal period (PD 7–49) known to be critical for glutamatergic system maturation. Locomotor activity in the “open-field” test, anxiety level in the elevated plus-maze test, and learning capacity in food rewarded spatial task were examined in young animals. Chronic MK-801 treatment produced a decrease of spontaneous motor and exploratory activity in 16- to 28-day-old rats. At the same time, a hyperlocomotion in response to acute administration of MK-801 was observed as well. Spatial learning of MK-801-treated rats was found to be negatively affected. Treated rats were able to respond to stress stimuli in the adequate manner but their anxiety level was found to be lower than in controls. Behavioral disturbances appeared to be temporary, and no such abnormalities could be detected at the age of 16 weeks. Thus, even mild chronic neonatal blockade of NMDA receptors may lead to a specific pattern of cognitive abnormalities presumably resulting from impairments of sensory information processing at the cortical–basal ganglia level.

The dopamine D 3 receptor mediates locomotor hyperactivity induced by NMDA receptor blockade

N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, like phencyclidine, generate schizophrenic-like symptoms in humans and behavioural abnormalities in animals, such as hyperactivity. We investigated the role of the dopamine D 3 receptor in locomotor hyperactivity produced in mice by dizocilpine (MK-801), another NMDA receptor antagonist, at a low dose (0.12 mg/kg). BP 897, a highly D 3 receptor-selective partial agonist, or nafadotride, a preferential D 3 receptor antagonist, both at low doses (1 mg/kg and lower), had no effects on spontaneous activity and completely inhibited MK-801-induced hyperactivity. Clozapine, an atypical antipsychotic, produced the same effect as BP 897 and nafadotride. Haloperidol, a typical antipsychotic, reduced both spontaneous activity and MK-801-induced hyperactivity. In D 3 receptor knockout mice, MK-801-induced hyperactivity was weaker than that observed in wild-type mice while BP 897 and nafadotride were inactive. On the contrary, the effects of clozapine and haloperidol, which target multiple receptors in addition to the D 3 receptor, were almost completely preserved in D 3 receptor knockout mice. Our results show that hyperactivity produced by a low dose of MK-801 is dependent upon D 3 receptor stimulation and constitutes the first simple response to assess the in vivo activity of D 3 receptor-selective drugs. In addition, since D 3 receptor antagonists and antipsychotics produced very similar effects, our results add to the growing evidence suggesting that D 3 receptor blockade might produce antipsychotic effects.

NMDA receptor regulation by amyloid-β does not account for its inhibition of LTP in rat hippocampus

Accumulation of amyloid-β peptide (Aβ) is widely believed to play a critical role in the pathogenesis of Alzheimer’s disease. Although amyloid-containing plaques are a key neuropathological feature of AD, soluble forms of Aβ can interfere with synaptic plasticity in the brain, suggesting that this form of the peptide may be responsible for much of the memory deficit seen early in the disease. Here, we investigate the mechanism underlying the effects of Aβ on long-term potentiation (LTP) in area CA1 of rat hippocampus. Extracellular field recordings were made in area CA1 of hippocampal slices taken from young, adult male rats. A non-toxic concentration of Aβ (200 nM) produced a rapid inhibition of LTP induced by 100 Hz stimulation while having no long-term effect on normal synaptic transmission. The same dose of Aβ had no effect on long-term depression (LTD) induced by 1200 pulses at 1 or 3 Hz. Picrotoxin had no effect on the inhibition of LTP, suggesting Aβ does not act by enhancing GABAergic transmission. Since the LTP induction in this study was dependent on N-methyl- d-aspartate (NMDA) receptor activation, we looked at the effect of Aβ on isolated NMDA receptor-mediated field potentials. Aβ produced a small but significant inhibition of NMDA receptor-mediated synaptic potentials (∼25%). However, a low dose of MK-801 (0.5 μM) that produced a similar inhibition of NMDA potentials had no effect on LTP induction but completely blocked LTD induction. These results suggest that Aβ does not inhibit LTP via effects on NMDA receptors, but rather interferes with a downstream pathway.

Administration of Low Doses of MK-801 During Ethanol Withdrawal in the Developing Rat Pup Attenuates Alcohol???s Teratogenic Effects

Administration of Low Doses of MK-801 During Ethanol Withdrawal in the Developing Rat Pup Attenuates Alcohol???s Teratogenic Effects

The effects of citicoline and/or MK-801 on survival, neurological and behavioral outcome of mice exposed to transient hyperglycemia and oligemic hypoxia

The effects of citicoline and/or low dose of MK-801 (sufficient to prevent the development of seizures) on survival, neurological and behavioral recovery following transient hyperglycemic–oligemic–hypoxic insult have been evaluated in mice. Neurological recovery was assessed semi-quantitatively on the third and the 10th day after the insult, and behavioral tests evaluating spontaneous locomotor activity, motor coordination and spontaneous alternation performance were performed on day 10. Neither drug given alone did influence survival rate, but the combination of MK-801 and higher citicoline dose decreased mortality on day 10. Behavioral performance was markedly compromised by the insult. Citicoline, but not MK-801, slightly but significantly improved behavioral outcome in all three tests. Conclusion: when brain ischemic insult is complicated with acute hyperglycemia, post-treatment with citicoline combined with MK-801 in low anti-convulsive dose improves survival and neurological recovery, and citicoline but not MK-801 enhances behavioral recovery.

The influence of MK-801 on bicuculline evoked seizures in adult mice exposed to transient episode of brain ischemia.

The aim of the study was to examine the role of NMDA receptors in modulation of protective effect against bicuculline toxicity after transient brain ischemia in mice. Animals were exposed for 30 min to bilateral clamping of the common carotid arteries (BCCA) in anaesthesia. MK-801 was administered intraperitoneally in two paradigms: a) acute treatment: twice, 1.0 mg/kg; 1 hour before clamping and 6 hours after re-circulation and b) chronic treatment: 0.1 mg/kg; started 24 hours after re-circulation and continued once daily for 13 days, the last injection was administered 24 hours before seizure induction. 14 days after BCCA, the animals were injected with bicuculline (3.5 mg/kg s.c). A significant decrease in seizure susceptibility could be observed in BCCA treated mice compared with sham-operated controls. Acute treatment with MK-801 did not affect seizure activity both in sham and BCCA mice. Chronic treatment with the drug potentiated anticonvulsant effect of brain ischemia but had no influence on seizure activity in sham-operated mice. The analysis of GABA content in brain tissue performed 14 days after BCCA showed a moderate increase in vehicle-treated mice and significant elevation after chronic treatment with MK-801. It can be suggested that NMDA receptors are not involved in the induction of a protective effect against bicuculline toxicity after transient brain ischemia. The prolonged treatment with low doses of MK-801 may potentiate a developed process in a mechanism of chemical preconditioning.

Differential effects of MK-801 on cerebrocortical neuronal injury in C57BL/6J, NSA, and ICR Mice

1. 1. Antagonists of the N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor, including [(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], dizocilpine maleate (MK-801), injure pyramidal neurons in the posterior cingulate/retrosplenial (PC/RS) cortex when administered systemically to adult rats and mice. 2. 2. These results have, to our knowledge, only been reported previously in Harlan Sprague Dawley albino rats and International Cancer Research (ICR) mice, an outbred albino strain. 3. 3. Male Non-Swiss Albino (NSA) mice, an albino outbred strain, and male C57BL/6J (B6) mice, a pigmented inbred strain, were injected systemically with 1 mg/kg of MK-801 in the first experiment. This dose of MK-801 reliably produces cytoplasmic vacuoles in neurons in layers III and IV of the PC/RS cortex in 100% of ICR mice treated. 4. 4. There was a significant difference in the number of vacuolated neurons in B6 and NSA mice, as assessed by ANOVA. The NSA were not significantly different than previously examined ICR mice, but the B6 had fewer vacuolated neurons than either of the two outbred strains. 5. 5. In the second experiment, male NSA, ICR, and B6 mice were injected systemically with a high dose, 10 mg/kg, of MK-801. This dose has been demonstrated to result in necrosis in the same population of neurons injured by lower doses of MK-801. 6. 6. An ANOVA indicated that there was a significant difference among the three strains of mice, and a Fisher's protected t revealed that the B6 mice were significantly different from both the NSA and ICR, but that, with our test, those two strains were indistinguishable 7. 7. Male ICR, NSA, and B6 mice were tested in the holeboard food search task 5 hours after 1 mg/kg of MK-801. There were significant differences between the strains in performance both pre and posttreatment. The effect of the drug was not statistically significant. 8. 8. These results suggest that there may be a genetically mediated difference in the reaction to NMDA receptor antagonists, a finding which may be important given the NMDA receptor hypofunction hypothesis for the etiology of schizophrenic symptoms.

The Delayed Effects of DTG and MK-801 on Latent Inhibition in a Conditioned Taste-Aversion Paradigm

The delayed effects of phencyclidine (PCP) have been shown to disrupt latent inhibition (LI) in a conditioned taste-aversion paradigm. In an attempt to understand the mechanism of this disruption, the delayed effects of the selective sigma receptor agonist 1,3-Di(2-tolyl)guanidine (DTG) and the selective NMDA receptor antagonist MK-801 on latent inhibition were assessed in the same paradigm. Water-deprived male rats were allowed access to either water (nonpreexposed; NPE) or 5% sucrose (preexposed; PE) for 30 min on 2 consecutive days. On the third day, animals were allowed access to sucrose and subsequently injected with lithium chloride. On the forth day, animals were allowed access to both sucrose and water. LI was assessed by comparing the percent sucrose consumed in PE and NPE groups on the fourth day. DTG (1.0, 5.0, or 10.0 mg/kg), MK-801 (0.5, 1.0, or 2.0 mg/kg), or vehicle was administered IP 20 h before preexposure (days 1 and 2) and conditioning (day 3). In vehicle-treated groups, PE animals consumed a significantly higher percent sucrose on the test day than NPE animals, indicating the presence of LI. DTG (10.0 mg/kg) and MK-801 (2.0 mg/kg) decreased the percent sucrose consumed by animals in the PE group to the level observed in the NPE group, indicating disrupted LI. However, this dose of MK-801 was found to produce a decrease in percent sucrose consumed in PE animals not treated with lithium chloride, indicating that the decrease observed in the LI paradigm could be due to MK-801–induced decrease in taste preference for sucrose rather than a disruption of LI. Lower doses of MK-801 that did not produce a decrease in taste preference for sucrose did not significantly disrupt LI. None of the doses of DTG tested altered taste preference for sucrose. These data suggest a role for sigma receptors in the previously observed PCP-induced disruption of LI. Published by Elsevier Science Inc., 2000

Effects of MK-801 on D1 dopamine receptor-mediated immediate early gene expression in the dopamine-depleted striatum

Previous work indicates that intrastriatal administration of MK-801 does not completely block D1 agonist-induced gene expression in dopamine-depleted rats. The present study examined the effects of systemic MK-801 on such gene expression. A low dose of MK-801 did not affect induction of c-fos or zif268. A high dose completely blocked induction of c-fos, but only slightly suppressed zif268. The data suggest that NMDA receptor activity may not always be necessary for D1-induced gene expression.

Glutamatergic Control of Food Intake in Pigeons: Effects of Central Injections of Glutamate, NMDA, and AMPA Receptor Agonists and Antagonists

The possible involvement of glutamatergic mechanisms in the control of food intake was studied in free-feeding and in 24-h food-deprived (FD24) pigeons for 1 h after intracerebroventricular (ICV) treatment with glutamate (Glu, 0, 50, 150, 300, and 600 nmol). Glu injections dose dependently induced decreases (30–65%) in food intake (FI) and feeding duration (FD), and increases in latency to start feeding (LSF) in FD24 animals, but not in free-feeding ones. None of these treatments affected noningestive behaviors (locomotion, sleep, and preening). In FD24 pigeons, ICV treatments with N-methyl- d-aspartic acid (NMDA, 0.1, 1, 4, 8, or 16 nmol) or d, l-α-amino-3-hydroxy-isoxazole proprionic acid (AMPA, 0.1, 1, 4, or 8 nmol) decreased FI and FD, but left LSF unchanged compared to vehicle-treated FD24 controls. Kainic acid (0.1, 0.5, and 1 nmol), or [ trans-(IS,3R)-ACPD-(5NH 4OH)] (ACPD, 0.1, 1, 4, 8, and 16 nmol) left unchanged the ingestive profile of FD24 pigeons. Pretreatment with the NMDA receptor antagonist MK-801 (15 nmol) and the AMPA-kainate receptor antagonist CNQX (390 nmol), 20 min before an ICV injection of Glu (300 nmol) induced a partial blockade of the Glu-induced decreases in FI and FD and completely inhibited the Glu-induced increase in LSF in FD24 pigeons. ICV injections of MK-801 (30 nmol) and of CNQX (780 nmol) increased FI and FD and reduced LSF in free-feeding pigeons. A lower dose of MK-801 (15 nmol) increased FI and FD, but not LSF. Conversely, a lower dose of CNQX (390 nmol) reduced LSF without changing FI or FD. These findings indicate the involvement of Glu as a chemical mediator in the regulation of food intake in the pigeon, possibly acting on multiple central mechanisms in this species through NMDA- and AMPA-sensitive Glu receptors.

MK‐801‐Induced Locomotor Activity in Long‐Sleep × Short‐Sleep Recombinant Inbred Mouse Strains: Correlational Analysis With Low‐Dose Ethanol and Provisional Quantitative Trait Loci

Low doses of the N-methyl-D-aspartate receptor (NMDAR) antagonist MK-801 (dizocilpine) or ethanol increase locomotor activity to a lesser extent in long-sleep (LS), than in short-sleep (SS), mice. LS mice also have fewer brain [3H]MK-801 binding sites than SS mice. In this study, LSXSS recombinant inbred (RI) mice were used to investigate whether different NMDAR densities contribute to differential MK-801 activation and whether common genes are involved in initial sensitivity to MK-801-and ethanol-induced activation. Locomotor activity was measured for 90 min after saline or MK-801 injection. Quantitative autoradiographic analysis of [3H]MK-801 binding was used to measure densities of NMDARs in seven brain regions. The ethanol (1-2 g/kg) activation scores from Erwin and colleagues (1997) were used for correlational analysis, as was their method for quantitative trait loci (QTL) analysis. Both saline and MK-801 (0.3 mg/kg, given intraperitoneally) induced a continuum of locomotor responses across the LSXSS RI strains. There was a 4-fold range of MK-801 difference scores (MK-801 score-saline baseline), with the RI 9 and RI 4 strains representing low and high responders, respectively. Dose-response experiments with these two strains confirmed that 0.3 mg/kg MK-801 produced significant activation, similar to previous results with LS and SS mice. However, unlike previous LS/SS results, lower densities of NMDARs were not observed in the RI 9 than in the RI 4 mouse brains. No significant genetic correlations were observed between MK-801-induced and ethanol-induced responses in the LSXSS RI mice. Two provisional MK-801 activation QTLs were identified (p < 0.01) on chromosomes 11 and 19, neither in common with those mapped for ethanol activation. Different densities of brain NMDARs are unlikely to account for the differential activation of LSXSS RI mice by MK-801. Additionally, in the RI mice either separate sets of genes regulate low dose MK-801- and ethanol-induced locomotor responses or the overlapping subset of genes controlling these two behaviors is small (< or =10%).

Involvement of the corticostriatal glutamatergic pathway in ethanol‐induced ascorbic acid release in rat striatum

The mechanism of ethanol-induced ascorbic acid (AA) release in striatum is not well understood. In the present work, the possible involvement of NMDA receptors in the corticostriatal pathway was studied by microdialysis coupled to high performance liquid chromatography with electrochemical detection. Ethanol (3.0 g/kg i.p.) stimulated significant striatal AA release to more than 200% above the baseline. This effect of ethanol could be partially antagonized by amantadine, a non-selective NMDA receptor antagonist and dopamine releaser, at a dose of 200 mg/kg i.p. and significantly antagonized by MK-801, a non-competitive NMDA receptor antagonist, at the doses of 0.5 and 1.0 mg/kg i.p. Furthermore, deafferentation of the glutamatergic projection from cortex to striatum by undercutting the prefrontal cortex completely eliminated ethanol-induced AA release in rat striatum. The basal level of AA in striatum could only be reduced by high doses of MK-801, but not by low doses of MK-801, amantadine or decortication. The results further confirm that NMDA receptors are involved in ethanol-induced AA release and provide the first evidence for the necessity of the activation of corticostriatal glutamatergic pathway in ethanol-induced AA release in rat striatum.

Dizocilpine maleate, MK-801, but not 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, NBQX, prevents transneuronal degeneration of nigral neurons after neurotoxic striatal–pallidal lesion

Unilateral neurotoxin lesion of rat caudate–putamen and globus pallidus resulted in delayed, transneuronal degeneration of GABAergic substantia nigra pars reticulata neurons. To explore whether the disinhibition of endogenous glutamate excitatory input played a role in the degeneration of substantia nigra pars reticulata neurons, animals with unilateral striatal–pallidal lesions received three daily intraperitoneal injections of either dizocilpine maleate (MK-801, 1 or 10 mg/kg), an N-methyl- d-aspartate glutamate receptor blocker, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, 30 mg/kg), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor blocker, that began 24 h after the striatal–pallidal neurotoxin lesion. Drug treatment affected neither the volume of the initial lesion nor the volume of striatal–pallidal glial fibrillary acidic protein immunoreactivity. Neuron number in the substantia nigra pars reticulata ipsilateral to the lesioned striatopallidum was reduced on average by 37% in untreated control rats, in low dose MK-801, and NBQX-treated rats ( P<0.0001). However, in animals treated with high doses of MK-801 there was no difference in the number of neurons in the substantia nigra pars reticulata ipsilateral or contralateral to the neurotoxin lesion. These data demonstrate that dose-related treatment with N-methyl- d-aspartate glutamate receptor blockers protects substantia nigra pars reticulata neurons, and suggests that glutamatergic mechanisms play a role in delayed transneuronal degeneration.