Haloperidol potentiates the EEG slowing of MK-801 despite blocking its motor effects: implications for the PCP model of schizophrenia

Haloperidol (HP) can block both the motor stimulation and the neurotoxic vacuolization of MK-801, suggesting that the two drugs have antagonistic brain actions. However, we show here that the modest EEG slowing produced by HP and MK-801 individually is massively potentiated when the drugs are combined. This finding challenges the argument for the PCP model of schizophrenia that assumes a general antagonism of neuroleptics and NMDA channel blockers. It further suggests that blockade of MK-801 motor effects is an inadequate test for antipsychotic drug actions. Our data indicate that intact function of D2 receptors (or other HP targets) is required to prevent generalized EEG slowing in the presence of NMDA channel blockade, a possibility of potential clinical interest.     

Bivalent effects of MK-801 on ethanol-induced sensitization do not parallel its effects on ethanol-induced tolerance.

The relationship between the effects of the N-methyl-D-aspartate (NMDA) antagonist MK-801 on acute responses to ethanol and its ability to block ethanol sensitization and tolerance was examined in DBA/2J mice. Cross-sensitization between these drugs was also studied. Repeated administration of 0.1 mg/kg MK-801 with ethanol potentiated, whereas 0.25 mg/kg attenuated, sensitization to ethanol's locomotor stimulant effects; rearing was similarly affected. There was evidence for cross-sensitization between ethanol and 0.25 mg/kg MK-801. MK-801 potentiated ethanol's ataxic effects in the grid test, but had no effect on tolerance to this effect. MK-801's effects on ethanol sensitization appeared to be related to its own behavioral effects, rather than NMDA receptor blockade per se. Further, these studies demonstrate dissociation between ethanol sensitization and tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Immediate and long-term effects of neonatal MK-801 treatment on nonspatial learning

These experiments observed the immediate and long-term effects of neonatal treatment with MK-801 on patterned single alternation (PSA), a form of nonspatial, memory-based learning. Rat pups were injected daily on postnatal days (PND) 7-19, with MK-801 (MK+) or the less active isomer of MK-801 (MK-) (0.25 mg/kg), and trained at either PND 22 or 60. Rats treated with MK+ or MK- and trained on PND 22 were significantly impaired in PSA when compared with the saline control. Beyond the learning impairment, MK+ rats showed an overall decreased running speed during training. They also presented an array of abnormal behaviors and significant weight loss. These nonassociative variables were determined for several doses (0.025, 0. 05, 0.1, 0.15, and 0.20 mg/kg) through PND days 22-25. Rats that received the threshold dose for secondary effects (0.025 mg/kg) also showed an overall decrease in running speed, but failed to show a significant nonspatial learning impairment on PSA. The PSA learning impairment was found to be not long lasting; rats trained at PND 60, after neonatally receiving the original high dose of MK-801, did not differ from controls.     

Aging and the effects of MK-801 on anoxic damage in rat hippocampal slices

A high-performance liquid chromatography assay for hydroxyurea in human serum was developed based on a commercial colorimetric assay kit for urea (Sigma Diagnostics). Serum (0.5 ml), spiked with methylurea as an internal standard, was treated with 70% perchloric acid. Supernatant (0.2 ml) was combined with 0.7 ml of BUN acid reagent and 0.6 ml of BUN color reagent. The resulting colored reactant (100 microl) was analyzed on a 300 x 3.9 mm Bondclone 10 C18 column coupled with a UV-Vis detector, at 449 nm. The mobile phase was 13% acetonitrile in water. Retention times of colored derivatives of hydroxyurea and methylurea were 6.5 and 12.2 min, respectively. The log-log calibration curve was linear from 0.0065 to 1.31 mM. Average accuracy was 99.9+/-4.0% and the intra- and inter-day error of assay did not exceed 11%.     

Modeling the effects of the NMDA receptor antagonist MK-801 on timing in rats.

The NMDA receptor antagonist MK-801 produces different effects on timing tasks. In particular, MK-801 produces an underestimation of duration when animals are tested with the differential reinforcement of low rate of responding (DRL) schedule and an overestimation of duration when animals are tested with the peak-interval (PI) procedure. The goal of this study was to develop a model-based explanation for this discrepancy. Two computer simulations were conducted via an implementation of scalar expectancy theory (SET). In Simulation 1, SET was used to provide a quantitative account of PI timing data. Simulation 2 used parameter estimates from Simulation 1 to predict effects of MK-801 on the DRL task. DRL predictions provided a close match to previous empirical data. Results of the simulations suggest that differences in the literature are likely due to inherent differences between PI and DRL tasks, rather than fundamental differences in timing. Overall, the role of NMDA receptors in timing appears to be multifaceted, impacting perception, memory, and decision processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Adenosine A1 and A2 receptor agonists significantly prevent the electroencephalographic effects induced by MK-801 in rats

Both N6-cyclopentyladenosine (CPA, adenosine A1 receptor agonist) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido-adenosi ne (CGS 21680, adenosine A2 receptor agonist) inhibited the electroencephalographic (EEG) effects induced by the noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine maleate (MK-801) in rats. While the inhibitory effects of CPA were evident at doses (0.1 and 0.5 mg/kg i.p.) devoid of intrinsic behavioral effects, CGS 21680 was effective only when administered at depressant doses (2 mg/kg i.p.). Since the effects induced by NMDA receptor antagonists may be regarded as a model of psychosis, these results suggest a possible role of adenosine receptor agonists as antipsychotics.     

Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses

Thalidomide, a hypnosedative drug introduced in the 1950s, has been used in a variety of dermatologic conditions during the past few decades. Although originally withdrawn from the world market on discovery of its teratogenic effect, it has since been selectively reintroduced for use in various disorders thought to have an autoimmune or inflammatory basis. A review of the literature focused on clinical uses of thalidomide in the treatment of dermatologic diseases was performed. Diseases for which thalidomide has been found effective include erythema nodosum leprosum, prurigo nodularis, actinic prurigo, discoid lupus erythematosus, aphthous stomatitis, Beh?et's syndrome, and graft-versus-host disease. Side effects such as teratogenicity and peripheral neuropathy remain its limiting factor. Thalidomide is a useful addition to the therapeutic armamentarium for treatment-resistant dermatoses as long as proper vigilance for adverse effects is maintained.     

MK-801 and male odours induce c-fos expression in the AOB of juvenile female mice

The odours of adult males, which accelerate the timing of puberty of female mice, activate c-fos in the accessory olfactory bulb (AOB). To test the hypothesis that NMDA receptors are involved in the male odour-induced increase in c-fos expression, we studied the effects of the non-competitive NMDA receptor agonist MK-801 on male odour-induced c-fos expression in the AOB of juvenile female mice. Surprisingly, MK-801 increased FOS-like immunoreactivity (FLI) within the AOB in the absence of male odour and had no effect on male odour-induced c-fos expression. We suggest that MK-801 increases AOB mitral cell activity by disinhibiting GABAergic granule cells, resulting in increased c-fos expression throughout the AOB.     

Comparative effects of the N-methyl-D-aspartate antagonist MK-801 and the calcium channel blocker KB-2796 on neurologic and metabolic recovery after spinal cord ischemia

The effects of maternal exposure to picrotoxin (PT) during the prenatal and postnatal periods of sexual brain differentiation were studied. Behavioral (sexual behavior), physical (sexual maturation, body, and organ weights) and neurochemical (striatal and hypothalamic monoamine and respective metabolite levels) data were assessed in the offspring of PT-treated dams. The following results were obtained: 1) sexual maturation as measured by the day of testis descent and testis weight comparison was unchanged; 2) a decrease in male sexual behavior occurred, as well as a decrease in body, ductus deferens, and seminal vesicle weights and in plasma testosterone levels of adult male offspring; 3) striatal dopamine (DA) and homovanillic acid (HVA) levels were decreased and hypothalamic norepinephrine (NE) levels were increased. These results indicate that perinatal exposure to PT during the critical periods of male brain sexual differentiation has long-term effects on the reproductive physiology and behavior of male rats.     

Comparison of the amnestic effects on NMDA receptor antagonist MK-801 and nitric oxide synthase inhibitors: L-NAME and L-NOARG in goldfish.

Investigations indicate that the induction of long-term potentiation (LTP) may be mediated by postsynaptic N-methyl-D-aspartate (NMDA) receptors and that the maintenance of LTP may be initiated by nitric oxide (NO), a retrograde messenger carrying signals backward from the postsynaptic to the presynaptic neuron. The present study compared amnestic effects of dizocilpine maleate (MK-801), an NMDA receptor antagonist, and nitro-L-arginine-methyl-ester (L-NAME) and N-nitro-L-arginine (L-NOARG), nitric oxide (NO) inhibitors, in goldfish, using active-avoidance conditioning as the learning paradigm. The results showed that MK-801 and NO inhibitors produced anterograde amnesia at doses that did not impair performance processes necessary for learning to occur. Furthermore, MK-801 did not produce retrograde amnesia, whereas L-NAME did, suggesting that MK-801 impaired learning whereas NO inhibitors impaired memory consolidation and possibly also learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stress and a glycinergic intervention interact in the modulation of MK-801-elicited mouse popping behavior

Cancer mortality in a population-based cohort of 10,322 parkinsonian patients (448 deaths observed during 1987 to 1994) was compared with that of the Italian province of Rome using the standardized mortality ratio (SMR). The overall cancer mortality risk was lower in this cohort than in the reference population (SMR, 56; 95% CI, 51 to 61). This reduction included most cancer sites as well as both smoking-related (SMR, 51; 95% CI, 42 to 60) and nonsmoking-related cancers (SMR, 58; 95% CI, 52 to 65). The observed reduction in cancer mortality risk in this cohort cannot be explained entirely by the hypothesis that smokers are less likely to develop PD.     

NMDA receptors modulate long-term habituation to spatial novelty: dose- and genotype-dependent differential effects of posttrial MK-801 and CPP in rats

To investigate the role N-methyl-D-aspartate (NMDA) receptors play in behavioral plasticity, adult male rats of the Naples high-(NHE) and low-excitability (NLE) lines, and of a random-bred Sprague-Dawley strain (NRB) received, the noncompetitive (MK-801:0.01 or 2.5 mg/kg) or the competitive (CPP: 0.01 or 5 mg/kg) NMDA receptor antagonists, or vehicle IP soon after a 10-min test in a Làt-maze. Retention was tested 1 week later. Habituation of activity and defecation score was monitored by the between-test decrement (LTH) in the frequency of corner-crossings (HA) and rearings (VA), with prevailing cognitive and noncognitive meaning, respectively, and of fecal boli. (i) In the NLE-rats, low and high doses of MK-801 facilitate LTH of HA, and a high dose of CPP facilitates LTH of HA. (ii) In the NRB-rats, MK-801 facilitates LTH of HA at a low dose and inhibits LTH of VA at a high dose, whereas CPP inhibits LTH of HA at a high dose only. In contrast, (iii) in the NHE-rats, high doses of MK-801 impair LTH of HA, and low doses of CPP facilitate LTH of HA. In conclusion, the dose- and genotype-dependent differential effects of allosteric and isosteric receptor blockade support the hypothesized modulatory role of NMDA receptors in behavioral plasticity; and the dissociation between retention of cognitive and noncognitive behavioral components suggests that NMDA receptors are involved in their parallel processing.     

Anticonvulsant and adverse effects of MK-801, LY 235959, and GYKI 52466 in combination with Ca2+ channel inhibitors in mice

This study was designed to investigate the influence of the calcium (Ca2+) channel inhibitors nicardipine, nifedipine, and flunarizine on the protective action of MK-801, LY 235959 [N-methyl-D-aspartate (NMDA) receptor antagonists], and GYKI 52466 (a non-NMDA receptor antagonist) against electroconvulsions in mice. Unlike nicardipine (15 mg/kg) or flunarizine (10 mg/kg) nifedipine (7.5 and 15 mg/kg) potentiated the protective potency of MK-801 (0.05 mg/kg), as reflected by significant elevation of the convulsive threshold (a CS50 value of the current strength in mA producing tonic hind limb extension in 50% of the animals). The protective activity of LY 235959 and GYKI 52466 was reflected by their ED50 values in mg/kg, at which the drugs were expected to protect 50% of mice against maximal electroshock-induced tonic extension of the hind limbs. Nicardipine (3.75 15 mg/kg), nifedipine (0.94-15 mg/kg), and flunarizine (2.5-10 mg/kg) in a dose-dependent manner markedly potentiated the antiseizure efficacy of LY 235959. Flunarizine (5 and 10 mg/kg) was the only Ca2+ channel inhibitor to enhance the protective action of GYKI 52466 against electroconvulsions. Except with MK-801 + flunarizine (motor performance) or GYKI 52466 + flunarizine (long-term memory), combination of NMDA or non-NMDA receptor antagonists with Ca2+ channel inhibitors produced an impairment of motor performance (evaluated in the chimney test) and long-term memory acquisition (measured in the passive avoidance task) as compared with vehicle treatment.     

The influence of nimodipine and MK-801 on the brain free arachidonic acid level and the learning ability in hypoxia-exposed rats

1. The influence of voltage dependent calcium channel blocker (VDCC), nimodipine and N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 on the brain free arachidonic acid (FAA) level and on the learning ability in hypoxia-exposed rats was examined. 2. Some animals were decapitated after cerebral hypoxia had been obtained and the brain FAA level was determined by gas chromatography. The other animals were trained in a passive avoidance procedure and were exposed to hypoxic conditions immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 hours later. 3. Various doses of nimodipine (0.03; 0.1; 0.3 and 1.0 mg/kg) and MK-801 (0.03; 0.1 and 0.3 mg/kg) had been injected 30 minutes before biochemical or behavioral procedures started. 4. It was found that hypoxia strongly increased the brain FAA level and impaired the retention of the passive avoidance response. 5. Pretreatment with 0.3 mg/kg and 1.0 mg/kg of nimodipine prevented the brain FAA accumulation. It has also been shown that all tested doses of nimodipine significantly improved the retention deficit in the animals exposed to hypoxia. 6. Neither the one of tested doses of MK-801 influenced significantly the increase of the brain FAA level and/or passive avoidance behavior in hypoxic animals. 7. These results confirm the hypothesis that the brain FAA accumulation and cognitive impairment, caused by hypoxia, are maybe associated with disturbances in calcium homeostasis and that nimodipine may be useful in ameliorating the hypoxia-induced brain tissue damage. Blocade of NMDA receptor-channel complex by MK-801 was not sufficient to prevent hypoxia-induced neuronal damage.     

Effects of amphetamine, morphine and dizocilpine (MK-801) on spontaneous alternation in the 8-arm radial maze

The induction of psychomotor activation, behavioural sensitization and of perseverative behaviours, resulting in reduced behavioural variability, have been proposed to be common properties of drugs of abuse. The present investigation tested whether these drug effects could be measured using spontaneous alternation in an 8-arm radial maze. Behavioural effects of repeated treatment with amphetamine (2 and 4 mg/kg, i.p.), morphine (1.25 and 10 mg/kg, i.p.) and the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.2 mg/kg, i.p.), on spontaneous alternation were evaluated in this paradigm. All drugs induced psychomotor activation. Sensitized as well as reduced locomotor activity could be observed after repeated treatment depending on drug and dose. Analysis of the sequences of arm entries revealed that all drugs induced perseverative locomotor patterns, but the pattern induced by amphetamine and morphine differed qualitatively from the pattern induced by MK-801.     

Spectroscopic properties and stability of the neurotoxic complex. Vipoxin and its components

The neurotoxin Vipoxin from the venom of Vipera ammodytes meridionalis is a complex between a toxic basic phospholipase A2 (PLA2) and a non-toxic acidic protein inhibitor (Inh). Tryptophan fluorescence parameters are determined for the complex and for its components. Iodide, caesium and acrylamide are not efficient quenchers of the Vipoxin indole emission. Increased accessibilities of tryptophans to ionic and neutral quenchers are found after the dissociation of the complex. Trp 20 and Trp 31 became more 'exposed' in the separated individuals proteins. The indole rings of the complex are located in a positively charged environment. Inspection of the Vipoxin X-ray model showed that the three tryptophyl side chains are located in the interface region between the enzyme and the inhibitor and are completely 'exposed' in the separated components of the complex. In Vipoxin an efficient 'interchain' energy transfer between tyrosyl and tryptophyl residues from different polypeptide chains occurs. Static quenching with acrylamide is also detected in PLA2 and Inh. The free energy changes deltaG D for the unfolding reactions of Vipoxin, PLA2 and Inh are determined in circular dichroism spectroscopy. The complex formation between the toxic PLA2 and the inhibitor increases deltaG HD2O to 23.5 kJ mol-1.     

The norm of self-interest and its effects on social action.

Four studies investigated whether people feel inhibited from engaging in social action incongruent with their apparent self-interest. Participants in Study 1 predicted that they would be evaluated negatively were they to take action on behalf of a cause in which they had no stake or in which they had a stake but held stake-incongruent attitudes. Participants in Study 2 reported both surprise and anger when a target person took action on behalf of a cause in which he or she had no stake or in which he or she held stake-incongruent attitudes. In Study 3, individuals felt more comfortable engaging in social action and expected others to respond more favorably toward their actions if the issue was described as more relevant to their own sex than to the opposite sex. In Study 4, the authors found that providing nonvested individuals with psychological standing rendered them as likely as vested individuals to undertake social action. The authors discuss the implications of these results for the relationship between vested interest, social action, and attitude–behavior consistency. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of NMDA receptor antagonist MK-801 on light-induced Fos expression in the suprachiasmatic nuclei and on melatonin production in the Syrian hamster

In mammals, circadian rhythms generated by the suprachiasmatic nuclei (SCN) are daily synchronized by a light-dark cycle. Photic information is transmitted to the SCN mainly through the direct retinohypothalamic tract, the neurotransmitters involved being excitatory amino acids. It is also commonly accepted that photoperiodic information coming from the retina via the SCN is transduced by the pineal into a nocturnal signal, i.e. melatonin production. Light exposure at night induces (1) an inhibition of melatonin synthesis and (2) an expression of c-fos in numerous cells of SCN. To determine the role of the NMDA receptor in these effects, we treated Syrian hamsters with ip injections of MK-801, a noncompetitive NMDA receptor antagonist. Several subpopulations of light-sensitive cells in the SCN are affected by MK-801. According to previous studies, MK-801 inhibits light-induced Fos immunoreactivity mainly in the most ventral part of the SCN. However, we observed that numerous other cells are still activated by light. When light is applied in the middle of the night, MK-801 pretreatment does not reduce Fos-ir in the dorsal SCN. At the beginning of the night, labeled cells in this part of the nucleus appear even more numerous after MK-801. We also found that MK-801 fails to reduce the light-induced inhibition of melatonin synthesis. Moreover, in control animals, which received no light stimulation, ip injection of MK-801 induces by itself a dose-dependent inhibition of melatonin production.