Modulation of MK-801 response by dopaminergic agents in mice

Various doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists, MK-801 (0.1–0.5 mg/kg) and ketamine (2.5–10 mg/kg), produced a dose-dependent increase in stereotypic behaviour in naive mice. MK-801 (0.1 mg/kg) and ketamine (2.5 mg/kg) potentiated the stereotypic response of apomorphine (0.1–0.5 mg/kg) in mice pretreated with reserpine (5 mg/kg, 24 h prior) and alpha-methyl-p-tyrosine (150 mg/kg, 1 h prior) but not in naive mice. SKF 38393, a D₁ dopamine agonist, enhanced whereas B-HT 920, a D₂ dopamine agonist, reduced the stereotypic response of MK-801 in naive mice. The response of MK-801 was blocked by pretreatment with haloperidol (0.5 mg/kg), molindone (2.5 mg/kg), clozapine (7.5 mg/kg) and SCH 23390 (0.1 mg/kg). The present data suggest involvement of endogenous DA transmission in the stimulant action of non-competitive NMDA antagonists in mice. Dopamine D₁ and D₂ receptor stimulation, respectively, exert opposing effects on the behavioural expression of MK-801 in mice.     

Characteristics of the ambulation-increasing effect of the noncompetitive NMDA antagonist MK-801 in mice: assessment by the coadministration with central-acting drugs.

Characteristics of the ambulation-increasing effect of MK-801, a non-competitive NMDA antagonist, were assessed through the coadministration of MK-801 with various central-acting drugs in mice. The MK-801 (0.3 mg/kg, i.p.)-induced ambulation-increment with a slight ataxia was maximum at around 50 min, and ambulation returned to the control level at about 3 hr after the administration. At 1 mg/kg, the mouse's activity transiently increased, followed by a decrease due to a marked ataxia, which was due to neither stereotypy nor convulsion, for 20-50 min, and then increased again; the ambulation-increment continued even at 4 hr after the administration. Coadministration of MK-801 (0.3 mg/kg, i.p.) with either methamphetamine (2 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), GBR-12909 (10 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) or morphine (10 mg/kg, s.c.) produced a significant enhancement of the effect. However, 0.1 mg/kg of MK-801 had no effect on the interaction with these drugs. On the other hand, the ambulation-increasing effect of MK-801 (0.3 mg/kg) was significantly reduced by haloperidol (0.3 and 0.1 mg/kg, s.c.), ceruletide (0.01 and 0.1 mg/kg, i.p.), reserpine (0.05 and 2 mg/kg, s.c., pretreatment 4 hr before) and nimodipine (1 and 3 mg/kg, i.p.), but it was scarcely modified by alpha-methyl-p-tyrosine (100 and 200 mg/kg, i.p., pretreatment 24 hr and 4 hr before), imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydro-biopterin (100 mg/kg, i.p.), pilocarpine (1 and 4 mg/kg, s.c.), N6-(L-2-phenylisopropyl)-adenosine (0.03 and 0.1 mg/kg, s.c.) and naloxone (1 and 5 mg/kg, s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice.

Cannabidiol, a nonpsychoactive constituent of the Cannabis sativa plant, has been reported to act as an agonist of the vanilloid 1 channel in the transient receptor potential family (TRPV1) and also to inhibit the hydrolysis and cellular uptake of the endogenous cannabinoid anandamide. Cannabidiol has also been reported to have potential as an antipsychotic. We investigated the effect of cannabidiol on sensorimotor gating deficits in mice induced by the noncompetitive NMDA receptor antagonist, MK-801. Sensorimotor gating is deficient in psychotic disorders such as schizophrenia and may be reliably measured by prepulse inhibition (PPI) of the startle response in rodents and humans. MK-801 (0.3-1 mg/kg i.p.) dose dependently disrupted PPI while cannabidiol (1-15 mg/kg i.p.), when administered with vehicle, had no effect on PPI. Cannabidiol (5 mg/kg i.p.) successfully reversed disruptions in PPI induced by MK-801 (1 mg/kg i.p.), as did the atypical antipsychotic clozapine (4 mg/kg i.p.). Pretreatment with capsazepine (20 mg/kg i.p.) prevented the reversal of MK-801-induced disruption of PPI by cannabidiol, providing preliminary evidence that TRPV1 receptors are involved in the reversal of MK-801-induced sensorimotor gating deficits by cannabidiol.     

Termination of pseudopregnancy in the rat alters the response to progesterone,chlordiazepoxide, and MK-801 in the elevated plus-maze

Rationale Allopregnanolone, a neurosteroid-reduced metabolite of progesterone, is a well-documented positive modulator of the -aminobutyric type A (GABA_A) receptor. As has been reported for other positive modulators of the GABA_A receptor, chronic exposure to neurosteroids is hypothesized to decrease GABA_A receptor function. Drawing from the literature on chronic exposure to benzodiazepines or alcohol, putative changes in N-methyl-d-aspartate (NMDA) receptor function are also expected after chronic neurosteroid exposure.Objectives To assess the sensitivity of the GABA_A and NMDA receptors after chronic elevation of neurosteroid produced by termination of pseudopregnancy in behavioral tests of anxiety and sensorimotor coordination.Methods Female rats ovariectomized on day 10 of pseudopregnancy were tested in the elevated plus-maze and on the rotor rod after an acute injection of progesterone (4 mg/0.2 ml, s.c.), chlordiazepoxide (5 or 15 mg/kg, i.p.), or MK-801 (0.025, 0.05, or 0.1 mg/kg, i.p.).Results Pseudopregnancy termination produced an anxiogenic-like response in the plus-maze; an acute injection of progesterone restored baseline levels of behavior in this test. Pseudopregnancy termination eliminated the anxiolytic-like, sedative, and ataxic effects of chlordiazepoxide. In contrast, pseudopregnancy termination produced an increased sensitivity to the anxiolytic-like and ataxic effects of MK-801.Conclusions The effects of pseudopregnancy termination on the behavioral response to positive modulators of the GABA_A receptor are consistent with results from studies in which chronic exposure to neurosteroids decreases the response to acute neurosteroid and benzodiazepine administration. However, unlike the enhanced glutamatergic tone resulting from discontinuation of chronic benzodiazepine or alcohol exposure, the termination of pseudopregnancy apparently decreases NMDA receptor function.     

Effects of antagonists at the NMDA receptor complex in two models of anxiety

The effects of an antagonist at the strychnine insensitive glycine site (5,7-dichlorokynurenic acid, i.c.v.), and of noncompetitive (MK-801, i.p.) and competitive (CGP 37849, i.p.; CGP 39551, i.p.; AP-7, i.c.v.) NMDA antagonists were compared with diazepam (i.p.) in two animal models of anxiety (the open field exploratory behavior of non-habituated rats, and the Vogel conflict test). All drugs when applied in appropriate doses increased punished drinking in the Vogel test, without producing any significant changes in free drinking and the stimulus threshold at their lowest anticonflict doses. The effective doses were as follows: diazepam 1.5 and 2.5 mg/kg; MK-801 0.005 and 0.01 mg/kg; CGP 39551 5.0 and 20.0 mg/kg; CGP 37849 1.0 and 2.5 mg/kg; 5,7-dichlorokynurenic acid 5.0 μg (i.c.v); AP-7 0.5 μg (i.c.v.). In the open field diazepam (0.05 mg/kg), MK-801 (0.1 mg/kg), CGP 37849 (0.01, 0.1, 1.0 mg/kg), and AP-7 2.5 μg (i.c.v.) significantly increased exploratory activity in the central sectors of the open field (anti-neophobic reaction), without changing motor activity of the rat. MK-801 at the highest tested dose of 0.2 mg/kg significantly stimulated animal locomotor activity. CGP 37849 in the largest dose examined (10 mg/kg) significantly depressed the motor behavior of rats. Overall, it appeared that different NMDA antagonists showed an anxiolytic-like profile, similar to that of the benzodiazepine diazepam. Among different NMDA receptor complex antagonists studied, CGP 37849 was characterized by the largest distinction between the doses showing an anxiolytic-like action in the open field test, and changing rat motor behavior.     

Drug discrimination analysis of NMDA receptor channel blockers as nicotinic receptor antagonists in rats

Rationale Antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors inhibit various phenomena associated with exposures to nicotine (e.g., tolerance, sensitization, dependence, and intravenous self-administration). These effects are often discussed in terms of nicotine-induced glutamate release with subsequent glutamate-dependent stimulation of dopamine metabolism and neuronal plasticity in brain areas critically involved in drug-addiction mechanisms. However, it is also well established that certain types of NMDA receptor antagonists (channel blockers) potently bind to nicotinic receptors and may act as nicotinic receptor antagonists.Objective The present study aimed to evaluate the discriminative-stimulus effects of the NMDA receptor channel blockers (+)MK-801, dextromethorphan, and memantine in rats trained to discriminate nicotine from its vehicle.Methods Adult male Wistar rats were trained to discriminate 0.6 mg/kg nicotine from saline under a two-lever, fixed-ratio 10 schedule of food reinforcement. During test sessions, injections of (+)MK-801 (0.03–0.3 mg/kg, i.p.), dextromethorphan (30 mg/kg, s.c.), or memantine (1–10 mg/kg, i.p.) were co-administered with s.c. nicotine (0.075–0.6 mg/kg; interaction tests) or saline (generalization tests). Additional interaction and generalization tests were conducted with the selective nicotinic receptor antagonists mecamylamine (0.1–3 mg/kg, s.c.) and MRZ 2/621 (0.3–10 mg/kg, i.p.), and the mGlu5 receptor antagonist MPEP (3–10 mg/kg, i.p.).Results In generalization tests, none of the compounds produced any appreciable levels of substitution for nicotine. The nicotine discriminative-stimulus control was dose dependently attenuated by mecamylamine (ED₅₀=0.67 mg/kg) and MRZ 2/621 (ED₅₀=9.7 mg/kg). Both agents produced a marked downward shift in the nicotine dose–response curve. Memantine and MPEP slightly attenuated nicotine discriminative-stimulus effects, while (+)MK-801 and dextromethorphan did not affect the nicotine-appropriate responding.Conclusions NMDA receptor channel blockers, such as (+)MK-801, dextromethorphan, and memantine, have minimal interactions with the discriminative-stimulus effects of nicotine.     

In vivo labelling of the NMDA receptor channel complex by [3H]MK-801

An in vivo radioligand binding assay for the N-methyl-D-aspartate (NMDA) receptor channel complex in the mouse brain has been developed using the non-competitive NMDA receptor antagonist [3H]MK-801. In vivo binding of [3H]MK-801 was displaced by MK-801 (ED50 = 0.17 mg/kg i.p.), (-)-MK-801 (1.0 mg/kg), thienylcyclohexylpiperidine (1.8 mg/kg), etoxadrol (5.1 mg/kg) and (+)-SKF 10,047 (34.5 mg/kg). The potency of these drugs in this in vivo binding assay was highly correlated (r = 0.97) with their functional effects as antagonists of N-methyl-DL-aspartate-induced tonic convulsions.     

Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test

This study investigated the involvement of the imidazoline receptors in the antidepressant-like effect of agmatine in the forced swimming test. The antidepressant-like effects of agmatine (10 mg/kg, i.p.) in the forced swimming test was blocked by pretreatment of mice with efaroxan (1 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I2/alpha2-adrenoceptor antagonist) and antazoline (5 mg/kg, i.p., a ligand with high affinity for the I2 receptor). A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with clonidine (0.06 mg/kg, i.p, an imidazoline I1/alpha2-adrenoceptor agonist), moxonidine (0.5 mg/kg, i.p., an imidazoline I1/alpha2-adrenoceptor agonist), antazoline (1 mg/kg, i.p.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist), but not with efaroxan (1 mg/kg, i.p.) and idazoxan (0.06 mg/kg, i.p.). Pretreatment of mice with yohimbine (1 mg/kg, i.p., an alpha2-adrenoceptor antagonist) blocked the synergistic antidepressant-like effect of agmatine (0.001 mg/kg, i.p.) with clonidine (0.06 mg/kg, i.p). A subeffective dose of MK-801 (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with antazoline (5 mg/kg, i.p.), but not with efaroxan (1 mg/kg, i.p.) or idazoxan (0.06 mg/kg, i.p.). In conclusion, this study suggests that the anti-immobility effect of agmatine in the forced swimming test is dependent on its interaction with imidazoline I1 and I2 receptors.     

Activation of mesolimbic dopamine function by phencyclidine is enhanced by 5-HT(2C/2B) receptor antagonists: neurochemical and behavioural studies

Administration of the non-competitive NMDA receptor antagonists phencyclidine (PCP) (0.6-5 mg/kg s.c.) and MK-801 (0.1-0.8 mg/kg s.c. ) dose-dependently increased locomotor activity in the rat. Pre-treatment of rats with SB 221284 (0.1-1 mg/kg, i.p.) a 5-HT(2C/2B) receptor antagonist or SB 242084 (1 mg/kg, i.p.) a selective 5-HT(2C) receptor antagonist, doses shown to block mCPP induced hypolocomotion, significantly enhanced the hyperactivity induced by PCP or MK-801. Neither compound altered locomotor activity when administered alone. Furthermore, systemic administration of PCP (5 mg/kg s.c.) increased nucleus accumbens dopamine efflux in the rat to a maximum of approximately 220% of basal, 40-60 min after administration. Pre-treatment with the 5-HT(2C/2B) receptor antagonist SB 221284 (1 mg/kg, i.p.) and the 5-HT(2C) receptor antagonist SB 242084 (1 mg/kg i.p.) failed to affect nucleus accumbens dopamine efflux per se but significantly enhanced the magnitude and duration of the increase induced by PCP. However, the time course of the neurochemical and behavioural effects were qualitatively and quantitatively different, suggesting the potential involvement of other neurotransmitter pathways. Nevertheless, the present results provide behavioural and neurochemical evidence which demonstrate that, in the absence of effects per se, blockade of 5-HT(2C) receptors enhanced the activation of mesolimbic dopamine neuronal function by the non-competitive NMDA receptor antagonists PCP and MK-801.     

Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N-methyl-D-aspartate receptor antagonists: preferential involvement of the NR2B rather than NR2A subunit

The non-competitive NMDA receptor antagonist phencyclidine (PCP) is known to produce a discriminative stimulus in rats. The first aim of the present study was to investigate which NMDA receptor subtype(s) is involved in this effect of PCP. Rats were trained to discriminate PCP (2 mg/kg; i.p.) from saline in a two lever operant task. The NMDA channel blocker, (+)MK-801 (0.1 mg/kg; i.p.) and the competitive NMDA receptor antagonist SDZ 220-581 (3 mg/kg; i.p.) produced 76% of PCP-lever selection (ED50=0.045 and 2 mg/kg, respectively), whereas their respective inactive enantiomers (-)MK-801 (0.025-0.1 mg/kg) and SDZ 221-653 (2-5 mg/kg) induced less than 30% of PCP-appropriate responding. Another competitive NMDA antagonist, SDZ EAB-515 (30 mg/kg; i.p.), induced 63% of PCP-lever responding (ED50=23.48 mg/kg). The selective antagonist of NMDA receptors containing the NR1A/NR2B-subunits Ro 25-6981 (20 mg/kg; i.p.) resulted in a complete substitution (more than 80% of PCP-lever selection) for PCP (ED50=8.59 mg/kg). In contrast, the NR1A/NR2A NMDA receptor-preferring antagonist NVP-AAM077 (2-10 mg/kg; i.p.) failed to produce PCP-like discriminative stimuli. At high doses SDZ 220-581 (ED50=2.44), NVP-AAM077 (ED50=8.33) and SDZ EAB-515 (ED50=25.81) decreased the performance of the rats in this operant task. The ability of these NMDA receptor antagonists to disrupt the prepulse inhibition (PPI) of the startle response and to alter locomotor activity was also studied. PCP (0.5-2 mg/kg; s.c.), SDZ 220-581 (0.5-5 mg/kg; s.c.), SDZ EAB-515 (1-30 mg/kg; i.p.) and Ro 25-6981 (5-20 mg/kg; i.p.) disrupted PPI and at high doses produced hyperlocomotion. In contrast, NVP-AAM077 (5-20 mg/kg; i.p.) did not disrupt PPI and reduced locomotor activity. In conclusion, it appears that the NMDA receptor containing the NR2B, rather than the NR2A subunit, may play a major role in the PCP-like discriminative stimulus. In addition, sensory motor gating disturbances associated with NMDA antagonists do not seem to result from a blockade of NR1/NR2A-containing NMDA receptors.     

Antagonism of caffeine-induced convulsions by ethanol and dizocilpine (MK-801) in mice

Ethanol (1 and 2 g/kg, i.p.) and MK-801 (1 mg/kg, i.p.), N-methyl-D-aspartate (NMDA) receptor antagonist, offered protection against caffeine-induced convulsions in mice. Subeffective doses of ethanol (0.5-g/kg, i.p.) and MK-801 (0.5 mg/kg, i.p.) when administered concurrently, did not provide a facilitatory anticonvulsant action against caffeine-induced convulsions. Ethanol (0.5 g/kg, i.p.) when administered concurrently with adenosine (100 mg/kg, i.p.) or dipyridamole (5 mg/kg, i.p.) elicited a facilitatory anticonvulsant action. However, concurrent administration of subeffective doses of MK-801 (0.5 mg/kg i.p.) with adenosine (100 mg/kg, i.p.) did not offer a facilitatory anticonvulsant action against caffeine-induced convulsions. The protective effect of ethanol (1 g/kg, i.p.) against caffeine-induced convulsions was reversed by an imidazobenzodiazepine, Ro 15-4513 (4 mg/kg, i.p.). Ro 15-4513 did not produce any proconvulsant effect with caffeine. It is suggested that ethanol and MK-801 elicit their anticonvulsant actions against caffeine-induced convulsions through different receptor mechanisms and that the anticonvulsant action of ethanol may be partly attributed to its ability to act via central adenosinergic mechanisms.     

The NMDA receptor antagonist MK-801 prevents imipramine-induced supersensitivity to quinpirole.

Chronic treatment with imipramine enhanced the locomotor stimulant response to quinpirole (0.3 mg/kg s.c.), a dopamine D2/D3 receptor agonist. Chronic, but not acute, blockade of the NMDA receptor with the non-competitive antagonist MK-801 (0.3 mg/kg i.p.) prevented the imipramine-induced potentiation of the quinpirole effect. The results suggest that NMDA receptors play a role in the development of supersensitivity to dopamine receptor agonists produced by chronic antidepressant treatment.     

The effects of an acute challenge with the NMDA receptor antagonists,MK-801, PEAQX,and ifenprodil,on social inhibition in adolescent and adult male rats

Rationale

NMDA antagonists consistently produce social inhibition in adult animals, although effects of these manipulations on social behavior of adolescents are relatively unknown.

Objectives

The aim of this study was to assess potential age differences in the socially inhibitory effects of the non-competitive NMDA antagonist, MK-801, as well as NR2 subunit selective effects, given the regional and developmental differences that exist for the NR2 subunit during ontogeny.

Methods

In separate experiments, adolescent and adult male Sprague–Dawley rats were treated acutely with MK-801 (0, 0.05, 0.1, 0.2 mg/kg, i.p.), the NR2A antagonist, PEAQX (2.5, 5, 10, 20 mg/kg, s.c.), or the NR2B antagonist, ifenprodil (1.5, 3, 6, 12 mg/kg, i.p.), 10 min prior to a social interaction test.

Results

Adolescents required higher doses of MK-801 (0.1 and 0.2 mg/kg) to induce social suppression, whereas adults demonstrated reductions in social activity after all doses. Likewise, adolescents required higher doses of ifenprodil (6 and 12 mg/kg) to produce social inhibitory effects relative to adults (all doses). In contrast, adults were less sensitive to PEAQX than adolescents, with adults showing social inhibition after 20 mg/kg whereas adolescents showed this effect following 10 and 20 mg/kg. Although locomotor activity was generally reduced at both ages by all drugs tested, ANCOVAs using locomotor activity as a covariate revealed similar patterns of social inhibitory effects.

Conclusions

Adolescents are less sensitive than adults to the disruption of social behavior by NMDA and NR2B-selective receptor antagonism, but not by an NR2A antagonist—age differences that may be related to different subunit expression patterns during development.     

Effects of ketamine, MK-801, and amphetamine on regional brain 2-deoxyglucose uptake in freely moving mice.

Although the pathophysiology of schizophrenia remains unclear, behavioral effects in humans induced by N-methyl-D-aspartate (NMDA) antagonists, such as ketamine, provide direction for formulating new pharmacologic models of the illness. The purpose of the present study was to clarify the roles of NMDA receptor antagonism, as well as dopamine-releasing properties of ketamine, in regional brain metabolic activity and behavioral responses in mice. The effects of acute administration of ketamine (30 mg/kg, i.p.) were compared with those of the more selective non-competitive NMDA antagonist MK-801 (0.3 and 0.5 mg/kg, i.p.), and amphetamine (4 mg/kg, i.p.) on regional brain [14C]-2-deoxyglucose (2-DG) uptake, by using a high resolution autoradiographic technique in the freely moving mice. Both ketamine and MK-801 induced substantial and similar neuroanatomically selective alterations in regional 2-DG uptake. Remarkable increases in 2-DG uptake in response to the NMDA antagonists were seen in limbic cortical regions, hippocampal formation, nucleus accumbens, select thalamic nuclei, and basolateral amygdala. The behavior of mice given amphetamine was similar to that of mice given MK-801. However, the brain activity patterns induced by amphetamine were distinctly different from those observed after ketamine and MK-801 treatment. These results suggest that generalized behavioral activation and increased dopamine release are insufficient to account for the ketamine-induced alterations in regional brain metabolism, and that the effects of ketamine on 2-DG uptake are likely related to a reduction in NMDA receptor function. The data also suggest that ketamine-induced changes in 2-DG uptake may provide a useful paradigm for translational research to better understand the pathophysiology of schizophrenia.     

Differential antagonism of the stimulant effects of MK-801 and methamphetamine by ceruletide: evaluation by discrete shuttle avoidance response in mice.

A noncompetitive NMDA antagonist MK-801 (0.03-0.3 mg/kg, i.p.) increased the response rate of mice trained under the discrete shuttle avoidance situation to a degree similar to the increase by methamphetamine (0.1-1 mg/kg, i.p.). The cholecystokinin-like decapeptide ceruletide significantly reduced the response-increasing effect of MK-801 (0.1 mg/kg) at 0.001 micrograms/kg; however, only 10 micrograms/kg of ceruletide, which per se inhibited the response, attenuated that of methamphetamine (0.3 mg/kg). The coadministration of MK-801 (0.1 mg/kg) and methamphetamine (0.3 mg/kg) produced no potentiation of the effect, and almost the same effect was maintained even after the additional administration of ceruletide (0.1 microgram/kg).     

Effects of dizocilpine (MK-801) and ethanol on the EEG and event-related potentials (ERPS) in rats.

Recent neurophysiological data have suggested an interaction of ethanol (EtOH) with the glutamate-NMDA receptor complex. For instance, low levels of alcohol have been found to inhibit the ion current, activated by NMDA in in vitro preparations. The present study extends these paradigms in order to evaluate the electrophysiological effects of ethanol and the nonspecific NMDA receptor antagonist, dizocilpine (MK-801) in awake, conscious rats. Twenty Wistar rats were stereotaxically implanted with electrodes, aimed at dorsal hippocampus, amygdala, thalamus and frontal cortex. Rats received the following drugs: saline (s.c.), 0.01 and 0.1 mg/kg MK-801 (s.c.); EtOH, 0.75 g/kg (i.p.); 0.75 kg EtOH plus 0.01 mg/kg MK-801; 0.75 g/kg EtOH plus 0.10 mg/kg MK-801. Five minutes of EEG was collected and event-related potentials (ERPs) recorded in response to an auditory "oddball" paradigm. Spectral analysis revealed that MK-801 (0.1 m/kg) produced significant increases in low frequency EEG components, at all sites (1-6 Hz) and decreases in higher frequencies (16-32 Hz). Whereas ethanol (0.75 g/kg) produced decreases in power in all frequency bands. The combined administration of EtOH and MK-801 produced some antagonistic effects on the EEG in the low frequency range. Evaluation of ERPs revealed that MK-801 (0.1 mg/kg) produced significant decreases in amplitude of the N1 and P2 components in the cortex, decreases in the P1 and N2 in the thalamus and a profound decrease in the P3 components in hippocampus and amygdala. Ethanol was also found to produce decreases in the N1 component in cortex. The administration of MK-801 and ethanol together did not produce significant interactions on ERPs. These studies suggest that antagonism of the NMDA receptor by MK-801 may produce some effects similar to those of ethanol, however, their combined administration did not produce synergistic effects within these dose ranges.     

Effects of olanzapine, sertindole and clozapine on MK-801 induced visual memory deficits in mice

We investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on visual recognition memory using the novel object recognition (NOR) test in naive and MK-801-treated animals. The effects of drug treatment on locomotion and anxiety were also determined using the open field test.Male Balb-c mice were treated with olanzapine (0.2, 0.4 and 0.6 mg/kg; i.p.), sertindole (0.63, 1.3 and 2.5 mg/kg; s.c.) or clozapine (0.5 and 1 mg/kg; i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg; i.p.) administration. Olanzapine treatment decreased the ratio index in the NOR test, whereas sertindole and clozapine had no effect in naive mice. MK-801-induced cognitive impairment was reversed by treatment with olanzapine, sertindole or clozapine. While olanzapine, sertindole and clozapine had no effect on the anxiety of naive mice as determined by the open field test, MK-801 significantly increased the total distance traveled, time spent in the center zone and the velocity of the animals. MK-801-induced effects on locomotion and anxiety in the open field test were reversed by olanzapine, sertindole or clozapine treatment. The results of the present study demonstrated that olanzapine, sertindole and clozapine improved cognition in MK-801 treated mice, and indicate that these drugs have a potential to improve cognition in schizophrenia.     

The anticonflict effect of MK-801, an NMDA antagonist: investigation by punishment procedure in mice

The NMDA antagonist MK-801 at 0.3 mg/kg, i.p. increased the punished response under a MULT VI 1.5/FR 5-punishment schedule of food reinforcement in mice. Furthermore, although neither MK-801 (0.1 mg/kg, i.p.) nor diazepam (0.25 mg/kg, s.c.) was without effect when separately administered, a significant increase in the punished response appeared after the combined administration of these two drugs. The present results suggest that MK-801 not only shows an anticonflict effect, but also enhances the anticonflict effect of benzodiazepine anxiolytics in mice.     

Differential effects of CGP 37849 and MK-801, competitive and noncompetitive NMDA antagonists,with respect to the modulation of sensorimotor gating and dopamine outflow in the prefrontal cortex of rats

In the present study we compared effects of the competitive and non-competitive NMDA antagonists CGP 37849 and MK-801, respectively, on sensorimotor gating in rats, measured as prepulse-induced inhibition of the acoustic startle response, and the outflow of dopamine in the rat prefrontal cortex. CGP 37849 (10, 20 mg/kg), decreased the amplitude of the acoustic startle response, but was without effect on the prepulse-induced inhibition of the acoustic startle response. MK-801 (0.4 but not 0.2 mg/kg) enhanced the amplitude of the acoustic startle response and its doses of 0.2 and 0.4 mg/kg markedly attenuated the prepulse-induced inhibition of the acoustic startle response. The effects of MK-801 (0.4 mg/kg) on the prepulse-induced inhibition of the acoustic startle response were not antagonized by the selective antagonists of D-2 and D-1 dopaminergic receptors, S(–)sulpiride (25 mg/kg) and SCH 23390 (0.1 mg/kg), respectively. When given alone, S(–)sulpiride attenuated the amplitude of the acoustic startle response and failed to altered the prepulse-induced inhibition of the acoustic startle response. SCH 23390 (0.1 mg/kg) failed to alter the amplitude and prepulse-induced inhibition of the acoustic startle response. The effects of CGP 37849 and MK-801 also differed with respect to dopamine outflow. MK-801 (0.2 and 0.4 mg/kg) enhanced the outflow of dopamine in the rat prefronatl cortex, while CGP 37849 (10 and 20 mg/kg) was without any effect on the extracellular concentration of dopamine. Our data indicate that the blockade of phencyclidine binding sites, exerted by the noncompetitive antagonist MK-801, evoked effects qualitatively different from those induced — via blockade of the NMDA recognition — by the competitive NMDA receptor antagonist CGP 37849. It is postulated that — in contrast to the non-competitive antagonist of NMDA receptors — the competitive NMDA antagonist CGP 37849 is/ should be devoid of psychotomimetic and abusing properties. It is also evident that disruption of sensorimotor gating in rats induced by MK-801 does not involve any dopaminergic mechanisms, since it is not modulated by drugs blocking D-1 and D-2 dopamine receptors. Correspondence to: K. Wdzony at the above address     

Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test

Lurasidone (SM-13496) is a novel atypical antipsychotic with high affinities to dopamine D2, serotonin 5-HT7, 5-HT2A, 5-HT1A receptors and alpha2C adrenoceptor. In this study, the effects of lurasidone on the rat passive-avoidance response and its impairment by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) were evaluated and compared with those of other antipsychotics. The passive-avoidance response was examined by measuring the step-through latency, 1 day after the animals received foot-shock training. When given before the training session, lurasidone did not affect the passive-avoidance response at any dose tested (1-30 mg/kg, p.o.). All the other atypical antipsychotics examined (i.e., risperidone, olanzapine, quetiapine, clozapine and aripiprazole), however, significantly reduced the step-through latency at relatively high doses. A pre-training administration of lurasidone significantly and dose-dependently reversed the MK-801-induced impairment of the passive-avoidance response. At doses lower than those that affected the passive-avoidance response, risperidone, quetiapine, and clozapine partially reduced the MK-801-induced impairment, whereas haloperidol, olanzapine, and aripiprazole were inactive. In addition, the post-training administration of lurasidone was as effective in countering the MK-801 effect as the pre-training administration, suggesting that lurasidone worked, at least in part, by restoring the memory consolidation process disrupted by MK-801. These results suggest that lurasidone is superior to other antipsychotics in improving the MK-801-induced memory impairment and may be clinically useful for treating cognitive impairments in schizophrenia.