NMDA Antagonist Dizocilpine Research Articles

Time-dependent effects of nicotine on reversal of dizocilpine-induced attentional impairment in female rats

Nicotine and nicotinic compounds have been found to attenuate the attentional impairments caused by the glutamate NMDA antagonist dizocilpine (MK-801). The timing of the nicotine effect on attention in rodents has not yet been determined. In the current study, we tested the interaction of dizocilpine with nicotine. Nicotine was given at a range of times (30 to 240 min) prior to dizocilpine administration and before testing on an operant signal detection task. Each rat was assessed with each dose timing. This protocol was repeated twice with one week between phases of testing. In the first phase, correct rejection performance was significantly impaired by 0.05 mg/kg of dizocilpine and this impairment was significantly attenuated by nicotine given sc 30–150 min prior to dizocilpine administration. The greater dizocilpine-induced percent correct rejection impairment seen during the first phase of drug challenge, was significantly attenuated by nicotine given 30 or 90 min before the start of the 1-h test session. During the second phase, the dizocilpine-induced repeated acquisition impairment was more modest. During this phase of testing nicotine administered 60, 90 or 150 min before testing significantly attenuated the dizocilpine-induced impairment. In both phases of testing, nicotine administration 240 min prior to testing was not seen to attenuate the dizocilpine-induced impairment. During the first phase but not the second phase, dizocilpine administration caused a significant impairment in percent hit. Nicotine was not found to have a significant effect in the second phase. Response omissions were significantly increased by dizocilpine during the first, but not the second phase. Nicotine was not found to have any significant effects on response omission. Overall, our data show that nicotine administration prior to dizocilpine administration was able to significantly improve dizocilpine-induced attentional impairment in a time-dependent manner.

Involvement of glutamatergic mechanisms in the median preoptic nucleus in the dipsogenic response induced by angiotensinergic activation of the subfornical organ in rats.

Experiments were done to investigate the role of glutamatergic systems in the median preoptic nucleus (MnPO) in the water ingestion induced by administration of angiotensin II (ANG II) in the subfornical organ (SFO) in the awake rat. Microdialysis methods were utilized to quantify the extracellular content of glutamate (Glu) in the region of MnPO. Microinjection of ANG II (10-10M) into the SFO significantly increased the release of Glu in the MnPO in the rats under the condition that water is available for drinking and the rats under the condition that water is not available for drinking. The amount of initial maximal increases in the Glu levels elicited by the ANG II injection was quite similar in drinking and non-drinking rats, whereas the duration of the response was much longer in non-drinking than in drinking rats. The amount of water ingestion in 20min immediately after the ANG II injection was significantly enhanced by previous injections of N-methyl-D-aspartate (NMDA, 10μM) into the MnPO, while the ANG II-induced water ingestion was attenuated by pretreatment with the NMDA antagonist dizocilpine (MK-801, 10μM). The amount of water intake elicited by the ANG II injection into the SFO was enhanced by previous injections of either the non-NMDA agonist kainic acid (KA, 50μM) or quisqualic acid (QA, 50μM) into the MnPO. On the contrary, the ANG II-induced drinking response was diminished by pretreatment with the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10μM) in the MnPO. Each injection of NMDA, KA, and QA into the MnPO produced drinking behavior. These results imply that the glutamatergic neural pathways to the MnPO may transmit the information for eliciting drinking in response to ANG II acting at the SFO. Our data further provide evidence that the ANG II-induced dipsogenic response may be mediated through both NMDA and non-NMDA glutamatergic receptor mechanisms in the MnPO.

Effects of NMDA antagonist dizocilpine (MK-801) are modulated by the number of distractor stimuli in the rodent odor span task of working memory.

The rodent odor span task (OST) uses an incrementing non-matching to sample procedure in which a series of odors is presented and selection of the session-novel odor is reinforced. An OST is frequently used to test the effects of neurobiological variables on memory capacity as the number of odors to remember increases during the course of the session. In this regard, one important finding has been that NMDA receptor antagonists selectively impair OST performance at doses that spare accuracy on control tasks. However, in many versions of the odor span task the number of stimuli to remember is confounded with the number of distractor odors presented to the rat on each trial. The present study compared the effects of the NMDA antagonist dizocilpine when the number of choices was held constant at two (one novel odor-S+ and one previously presented distractor odor-S-) and when the number of choice stimuli was permitted to increase up to 10 (one S+ and 9 S-). Dizocilpine impaired OST accuracy at doses that had no effect on a reference memory control task in both 2-choice and 10-choice conditions; however, the dose-response function was shifted to the left in the 10-choice tests. The impairments produced by dizocilpine were exacerbated as the memory load increased in both 2- and 10-choice conditions. These findings support the hypothesis that NMDA antagonism reduces the number of stimuli that rats can remember accurately, but the interaction between the effective DZP dose and the number of distractors shows that drug effects on OST performances may involve attentional factors in addition to memory capacity. The findings also demonstrate that variations in number of OST distractors can be used to alter sensitivity of the task.

Glutamatergic modulation of noradrenaline release in the rat median preoptic area

The present study was carried out to investigate whether glutamatergic receptor mechanisms modulate the release of noradrenaline (NA) in the region of the median preoptic nucleus (MnPO) using intracerebral microdialysis techniques in freely moving rats. Perfusion of N-methyl-d-asparatate (NMDA, 10 and 50μM) through the microdialysis probe significantly enhanced dialysate NA concentration in the region of the MnPO. Local perfusion of the NMDA antagonist dizocilpine (MK801, 10 and 50μM) did not change the basal release of NA in the MnPO area. MK801 (10μM) administered together with NMDA antagonized the stimulant effect of NMDA (50μM). Perfusion of the non-NMDA agonist quisqualic acid (QA, 10 and 50μM) or kainic acid (KA, 10 and 50μM) significantly increased the NA release in the MnPO area. Perfusion of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 and 50μM) had no effect on the NA release. CNQX (10μM) administered together with either QA (50μM) or KA (50μM) in the MnPO area prevented the stimulant effect of the agonists on the NA release. Nonhypotensive hypovolemia following subcutaneous injections of polyethylene glycol (PEG, 30%, 5ml) significantly elevated the NA level in the MnPO area. The PEG-induced elevation in the NA release was attenuated by perfusion of either MK801 (10μM) or CNQX (10μM). The present results suggest that glutamatergic synaptic inputs may act to enhance the release of NA in the MnPO area through both NMDA and non-NMDA receptors, and imply that these glutamatergic receptor mechanisms may be involved in the noradrenergic reguratory system for the body fluid balance.

Impairment of the anterior thalamic head direction cell network following administration of the NMDA antagonist MK-801.

Head direction (HD) cells, found in the rodent Papez circuit, are thought to form the neural circuitry responsible for directional orientation. Because NMDA transmission has been implicated in spatial tasks requiring directional orientation, we sought to determine if the NMDA antagonist dizocilpine (MK-801) would disrupt the directional signal carried by the HD network. Anterior thalamic HD cells were isolated in female Long-Evans rats and initially monitored for baseline directional activity while the animals foraged in a familiar enclosure. The animals were then administered MK-801 at a dose of .05 mg/kg or 0.1 mg/kg, or isotonic saline, and cells were re-examined for changes in directional specificity and landmark control. While the cells showed no changes in directional specificity and landmark control following administration of saline or the lower dose of MK-801, the higher dose of MK-801 caused a dramatic attenuation of the directional signal, characterized by decreases in peak firing rates, signal to noise, and directional information content. While the greatly attenuated directional specificity of cells in the high dose condition usually remained stable relative to the landmarks within the recording enclosure, a few cells in this condition exhibited unstable preferred directions within and between recording sessions. Our results are discussed relative to the possibility that the findings explain the effects of MK-801 on the acquisition and performance of spatial tasks.

Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats.

Nicotine has been well characterized to improve memory and attention. Nicotine is the primary, but not only neuroactive compound in tobacco. Other tobacco constituents such as anabasine and anatabine also have agonist actions on nicotinic receptors. The current study investigated the effects of anabasine and anatabine on memory and attention. Adult female Sprague-Dawley rats were trained on a win-shift spatial working and reference memory task in the 16-arm radial maze or a visual signal detection operant task to test attention. Acute dose-effect functions of anabasine and anatabine over two orders of magnitude were evaluated for both tasks. In the radial-arm maze memory test, anabasine but not anatabine significantly reduced the memory impairment caused by the NMDA antagonist dizocilpine (MK-801). In the signal detection attentional task, anatabine but not anabasine significantly attenuated the attentional impairment caused by dizocilpine. These studies show that non-nicotine nicotinic agonists in tobacco, similar to nicotine, can significantly improve memory and attentional function. Both anabasine and anatabine produced cognitive improvement, but their effectiveness differed with regard to memory and attention. Follow-up studies with anabasine and anatabine are called for to determine their efficacy as therapeutics for memory and attentional dysfunction.

Orphenadrine-induced convulsive status epilepticus in rats responds to the NMDA antagonist dizocilpine

BackgroundIdentification of new molecular targets as well as the new models recapitulating different aspects of pathophysiology of status epilepticus (SE) in humans might prove essential for the breakthrough in the efforts against pharmacoresistance in epilepsy. Recently, we described a new model of generalized convulsive SE induced with orphenadrine (ORPH) in rats with unique characteristics [5]. The current study was aimed at assessing the efficacy of a new generation antiepileptic drugs (AEDs) and some of the experimental agents in suppressing ORPH-evoked seizures in rats. MethodsORPH was administered intraperitoneally (ip) in the dose of 80mg/kg in male Wistar rats. The latency to first seizure, the number of seizure episodes and the duration of overt SE, as well as the incidence of deaths was scored with simultaneous electroencephalographic (EEG) recordings. ResultsORPH induced seizures in 100% of animals at a dose of 80mg/kg, associated with low mortality and good behavioural outcome. Among new generation AEDs: felbamate, levetiracetam, topiramate, lamotrigine and progabide did not affect the seizure incidence. Among the experimental drugs, only dizocilpine, the non-competitive NMDA antagonist, dose-dependently affected the occurrence of the SE (p<0.001). However, CGP-39551 competitive NMDA antagonist, the same as scopolamine and mecamylamine (muscarinic and nictotinic receptors antagonists, respectively) showed no effect. ConclusionsBased on the above findings, one may speculate that NMDA activation is partly involved in the proconvulsant activity of orphenadrine but may not be the primary pathomechanism. ORPH-induced seizures may provide an interesting option for studying novel targets for pharmacological interventions in status epilepticus.

Working memory in the odor span task: effects of chlordiazepoxide, dizocilpine (MK801), morphine, and scopolamine

A number of tasks are used to assess working memory in rodents, but the odor span task (OST) is unique in studying performance as a function of the number of stimuli to remember. The purpose of the present study was to better characterize the behavioral pharmacology of the OST by exploring the effects of several amnestic agents including an NMDA antagonist (dizocilpine), a positive GABA-A modulator (chlordiazepoxide), an anticholinergic compound (scopolamine), and as a negative control, an opiate receptor agonist (morphine). Rats were trained to perform on the OST which is a non-match-to-sample procedure with an incrementing number of sample odors to remember as the session progresses. Trials with a simple odor discrimination task (SD) were interspersed to provide a control for effects unrelated to memory load. All four drugs disrupted performances on the OST task in a dose-dependent fashion, but only the NMDA antagonist dizocilpine produced impairments that were clearly dependent on the number of stimuli to remember. Dizocilpine impaired OST performance at a dose (0.1 mg/kg) that did not affect SD, and that impairment depended on memory load. Chlordiazepoxide (3.0 mg/kg) also produced amnestic effects that were manifest by shorter memory spans and runs of correct responding. In contrast, morphine and scopolamine impaired OST accuracy only at doses that also disrupted SD (18.0 and 0.3 mg/kg, respectively). These results provide evidence of NMDA and benzodiazepine modulation of working memory as assessed by the OST.

Poster #224 THE PUTATIVE ANTIPSYCHOTIC ALSTONINE DECREASES GLUTAMATE UPTAKE IN RAT HIPPOCAMPAL SLICES

An imbalance between different neurotransmitter systems is involved in the pathophysiological processes underlying schizophrenia. Since the neurotensin (NT) system modulates the activity of several of these neurotransmitters, drugs acting upon the NT system may act as novel antipsychotic drugs. This hypothesis is supported by studies with NT in animal models. For example, intracranial injection of NT improves sensorimotor gating in rats [Feifel D, Minor KL, Dulawa S, Swerdlow NR. The effects of intra-accumbens neurotensin on sensorimotor gating. Brain Research 1997;760:80–4]. NT-mimetics, such as NT69L, have been developed which are more resistant to enzymatic degradation than the native NT peptide. In the present study, the potential antipsychotic properties of NT69L were evaluated in a rat pre-pulse inhibition (PPI) paradigm. PPI is a measure of sensorimotor gating where a weak auditory stimulus, or pre-pulse, inhibits the startle response to a strong stimulus, or pulse. Schizophrenic patients exhibit deficits in their PPI response. This condition can be mimicked in rats with psychotomimetic drugs and the resulting PPI deficit is reversed by antipsychotic drugs. NT69L (0.1–10 mg/kg i.p.) reversed disruptions of the PPI response induced by the NMDA antagonist dizocilpine (0.1 mg/kg s.c.) for at least 1-h post-injection, but did not reverse disruptions induced by the dopaminergic agonists apomorphine and d-amphetamine (0.5 and 5 mg/kg s.c., respectively). These results confirm that NT69L possesses antipsychotic-like activity and therefore could be beneficial in the treatment of schizophrenia.

Nerve growth factor and brain-derived neurotrophic factor but not granulocyte colony-stimulating factor, nimodipine and dizocilpine, require ATP for neuroprotective activity after oxygen–glucose deprivation of primary neurons

In previous work, we have demonstrated by radiolabeling, mass spectrometry and site-directed mutagenesis that nerve growth factor (NGF) as well as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2) are capable of ATP-binding and that this binding appears to be essential for their neuroprotective activity. In this study, we attempted to shed some light on the question whether ATP is a general prerequisite for neuroprotection. Therefore, we used the non-ATP-binding granulocyte colony-stimulating factor (GCSF), the calcium antagonist nimodipine and the NMDA antagonist dizocilpine to find out whether they need ATP for neuroprotection comparable to NGF and BDNF. However, ATP was not necessary for the neuroprotective effects of GCSF, nimodipine and dizocilpine on primary cultures of rat cortical neurons damaged by oxygen–glucose deprivation whereas neuroprotection was demonstrable for NGF and BDNF only when ATP was present in the culture medium at a concentration higher than ca. 0.4nmol/l. In circular dichroism studies ATP caused changes of the secondary structure of NGF but not of GCSF. Taken together, we suggest that ATP is not a general prerequisite for neuroprotectivity but some growth factors like NGF and BDNF can stimulate their receptors only if they have bound ATP.

The effect of the NMDA receptor antagonist dizocilpine on behavioral manifestations of serotonin and adrenergic antidepressants in rats

Glutamatergic neurotransmission has been implicated in affective disorders, possibly through the modulation of monoaminergic mechanisms. The aim of this study was to investigate the effect of coadministration of the noncompetitive NMDA antagonist dizocilpine (MK-801) with different, primarily noradrenergic and serotonergic antidepressants on forced swimming test (FST) and open-field behavior in rats. Acute administration of dizocilpine at doses of 0.02- 0.1 mg/kg did not show any effect in the open-field test or FST. Acute administration of citalopram (5 mg/kg), fluoxetine (20 mg/kg), desipramine (20 mg/kg) and maprotiline (20 mg/kg) did not influence FST, although coadministration of dizocilpine with serotonergic but not noradrenergic antidepressants caused a significant reduction of immobility. In the open-field test, fluoxetine had no effect on horizontal activity but significantly reduced the number of rearings. The coadministration of dizocilpine with fluoxetine elicited significant horizontal locomotor activation and attenuated the effect of fluoxetine on vertical activity. The combined administration of other antidepressants with dizocilpine tended to increase horizontal activity similar to that recorded with fluoxetine plus dizocilpine, but these effects were not statistically significant. Thus, the present results indicated that the coadministration of serotonergic antidepressants with NMDA receptor antagonists may induce faster and more pronounced antidepressant activity when compared to treatment with antidepressants alone. In contrast, the NMDA antagonists did not potentiate the antidepressant-like effects of noradrenergic antidepressants.

The neurotensin agonist NT69L improves sensorimotor gating deficits in rats induced by a glutamatergic antagonist, but not by dopaminergic agonists

An imbalance between different neurotransmitter systems is involved in the pathophysiological processes underlying schizophrenia. Since the neurotensin (NT) system modulates the activity of several of these neurotransmitters, drugs acting upon the NT system may act as novel antipsychotic drugs. This hypothesis is supported by studies with NT in animal models. For example, intracranial injection of NT improves sensorimotor gating in rats [Feifel D, Minor KL, Dulawa S, Swerdlow NR. The effects of intra-accumbens neurotensin on sensorimotor gating. Brain Research 1997;760:80–4]. NT-mimetics, such as NT69L, have been developed which are more resistant to enzymatic degradation than the native NT peptide. In the present study, the potential antipsychotic properties of NT69L were evaluated in a rat pre-pulse inhibition (PPI) paradigm. PPI is a measure of sensorimotor gating where a weak auditory stimulus, or pre-pulse, inhibits the startle response to a strong stimulus, or pulse. Schizophrenic patients exhibit deficits in their PPI response. This condition can be mimicked in rats with psychotomimetic drugs and the resulting PPI deficit is reversed by antipsychotic drugs. NT69L (0.1–10 mg/kg i.p.) reversed disruptions of the PPI response induced by the NMDA antagonist dizocilpine (0.1 mg/kg s.c.) for at least 1-h post-injection, but did not reverse disruptions induced by the dopaminergic agonists apomorphine and d-amphetamine (0.5 and 5 mg/kg s.c., respectively). These results confirm that NT69L possesses antipsychotic-like activity and therefore could be beneficial in the treatment of schizophrenia.

Evaluation of NMDA receptor models of schizophrenia: Divergences in the behavioral effects of sub-chronic PCP and MK-801

The hypothesis of hypo-functionality of NMDA receptors in schizophrenia originates from the observation that administration of the NMDA antagonist phencyclidine (PCP) induces psychotic states that closely resemble schizophrenic symptoms and that persist after drug discontinuation. A large number of animal studies have used PCP and the NMDA antagonist dizocilpine (MK-801) almost interchangeably to model schizophrenia. However, PCP interacts with pharmacological targets other than NMDA receptors that are not affected by MK-801. In addition, although acute administration of either compound produces similar effects in animals, there is little information whether withdrawal from chronic MK-801 causes behavioral deficits that mimic schizophrenia symptoms as in the case of PCP. To clarify this issue, we compared the following behaviors in rats subjected to withdrawal from sub-chronic administration (2 × 7 days) of either PCP (5 mg/kg, i.p.) or MK-801 (0.5 mg/kg, i.p.): (1) working memory in a variable-delayed alternation task in a T-maze, (2) social interaction, and (3) motor activity in response to a (a) novel environment, (b) mild stressor, and (c) d-amphetamine challenge. Withdrawal from sub-chronic PCP caused a delay-dependent impairment of working memory, reduced social interaction and enhanced d-amphetamine-induced motor activity. These results were not replicated in animals sub-chronically treated with MK-801, which displayed only a slight decrease in social interaction. These data suggest that pharmacological antagonism at NMDA receptors is not sufficient to explain the full spectrum of PCP psychotomimetic properties.

A pharmacological MRI assessment of dizocilpine (MK-801) in the 3-nitroproprionic acid-lesioned rat

The NMDA-antagonist dizocilpine (MK-801) is known to have dissociative, neurotoxic and neuroprotective properties. Although its neuroprotective properties are well documented, at present only ex vivo autoradiography has demonstrated its activity in lesioned brains. We report here the use of pharmacological magnetic resonance imaging (phMRI) to visualise the neural substrates of MK-801 in normal control rats and in animals that received systemic 3-nitroproprionic acid (3-NPA) 2 weeks earlier. In control animals, this NMDA-antagonist resulted in activity in the hippocampus, retrospinal (RS) cortex, anterior cingulate and the medial prefrontal cortex (MPFC). Activity in the MPFC has been associated with the dissociative properties of this agent and has been suggested to be the neurological substrate of positive psychotic symptoms, whereas RS and hippocampus have been the main sites of neurotoxic actions of MK-801. In contrast, in animals with 3-NPA-lesions affecting the striatum, no activity in the MPFC was observed, but a positive BOLD signal in the striatum was apparent. Lesioned animals injected with saline did not show this pattern of activity indicating that it is not merely an artefact of the ongoing neurodegeneration. This striatal activity could therefore be a site of MK-801-mediated neuroprotection. phMRI therefore sheds further light on the in vivo activity of MK-801 which, in turn, may allow us to more fully understand the different actions of NMDA-antagonists.

Nicotine and clozapine effects on attentional performance impaired by the NMDA antagonist dizocilpine in female rats

Cognitive impairment is very prevalent in schizophrenia and is currently undertreated in most patients. Attentional deficit is one of the hallmark symptoms of schizophrenia. Antipsychotic drugs, which can be quite effective in combating hallucinations are often ineffective in reducing cognitive impairment and can potentiate cognitive impairment. Previously, we found that the antipsychotic drug clozapine impaired, while nicotine improved, the accuracy of rats performing a visual signal detection attentional task in normal rats. For the current study, in a model of cognitive impairment of schizophrenia with the NMDA antagonist dizocilpine (0.05 mg/kg), we examined the effects of clozapine and nicotine on significantly impaired attentional hit accuracy. This dizocilpine-induced impairment was significantly (p<0.05) reversed by either clozapine (1.25 mg/kg) or nicotine (0.025 mg/kg). Interestingly, when clozapine and nicotine were given together, they blocked each other's beneficial effects. When the effective doses of 1.25 mg/kg clozapine and 0.025 mg/kg nicotine were given together the combination no longer significantly reversed the dizocilpine-induced hit-accuracy impairment. Given that the great majority of people with schizophrenia smoke, the potential beneficial effects of clozapine on attentional function may be largely blocked by self-administered nicotine. In addition, there are promising results concerning the development of nicotinic treatments to reverse cognitive deficits including attentional impairment. This is supported in the current study by the reversal of the dizocilpine-induced attentional impairment by nicotine. However, in schizophrenia the efficacy of nicotinic treatments may be limited by co-treatment with antipsychotic drugs like clozapine. It will be important to determine which of the complex effects of clozapine and nicotine are key in reversing attentional impairment and how they block each other's effects for the development of therapy to combat the attentional impairment of schizophrenia.

Chlordiazepoxide and dizocilpine, but not morphine, selectively impair acquisition under a novel repeated-acquisition and performance task in rats

Some classes of drugs can selectively affect learning (i.e., acquisition of behavior) at doses that do not affect performance (i.e., previously learned behavior). Some drugs (e.g., benzodiazepines) show selective effects on acquisition across a wide variety of tasks. Other drugs [e.g., N-methyl-D-aspartate (NMDA) antagonists and opiate agonists], however, show selective effects under some tasks, but not others. The purpose of this study was to examine the effects of the NMDA-antagonist dizocilpine (0.01-0.3 mg/kg), the opiate-agonist morphine (1.0-17.0 mg/kg), and the benzodiazepine chlordiazepoxide (3.0-30.0 mg/kg) in rats under a novel repeated-acquisition and performance task. Nose pokes to a correct location within a 2x3 stimulus array on a computer touch screen were reinforced with food. In the acquisition component, the correct location changed across sessions but remained constant within sessions; in the performance component, the correct location was constant both across and within sessions. Both chlordiazepoxide and dizocilpine selectively impaired accuracy in the acquisition component at doses that did not affect accuracy in the performance component or overall response speed. Morphine, however, did not affect acquisition without affecting performance or response speed. These results with rats resembled those previously obtained for response-sequence learning in primates, rather than those previously reported for spatial learning in rats. Therefore, previous discrepancies in results for NMDA antagonists and opiate agonists across tasks probably were not a function of the species studied, but, rather, they more likely were a function of unique variables controlling acquisition within each task.

NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth.

Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.

Application of a novel Active Allothetic Place Avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze

Administration of a non-competitive NMDA antagonist dizocilpine (MK-801) was proposed to be an animal model of psychosis. NMDA-receptor blockade is accompanied by increased locomotion, behavioral deficits, and other changes resembling psychotic symptoms. However, the role of NMDA-receptors in organizing brain representations is not understood yet. We tested the effect of NMDA-receptor blockade by systemic administration of dizocilpine at two different doses (0.1 or 0.2 mg/kg) in a recently designed Active Allothetic Place Avoidance (AAPA), a task which requires rats to separate spatial stimuli from two continuously dissociated subsets. The effect of dizocilpine on learning in the AAPA task was compared with its effect on acquisition of the reference memory version of the Morris Water Maze task. Both doses impaired performance in the Morris Water Maze task, whereas only the higher dose impaired performance in the AAPA task. The Morris Water Maze appears to be more sensitive to dizocilpine-induced behavioral deficit than the AAPA task. These findings support the notion that these two tasks are differentially dependent on the NMDA-receptor function.

Guanosine selectively inhibits locomotor stimulation induced by the NMDA antagonist dizocilpine

Guanosine has been shown to modulate glutamate system by stimulating astrocytic glutamate uptake. Recent evidence suggest that the locomotor effects of NMDA receptor antagonists, an animal model of schizophrenia, is associated with activation of non-NMDA glutamatergic receptors caused by increased glutamate release. The present work was undertaken to evaluate whether guanosine could have influence on the hyperlocomotion induced in mice by dizocilpine (MK-801), a NMDA antagonist. We also evaluated the effect of guanosine on the hyperlocomotion induced by the indirect dopamine agonist amphetamine, and by the non-selective adenosine receptor antagonist caffeine. Guanosine (7.5 mg/kg) produced an attenuation of about 60% on the hyperlocomotion induced by dizocilpine (0.25 mg/kg), whereas it did not affect the hyperlocomotion induced by amphetamine (5 mg/kg) or caffeine (30 mg/kg). Guanosine pre-treatment did not affect total spontaneous locomotion in all experiments. To test neuronal pathway selectivity, we evaluated MK-801 against guanosine in a working memory paradigm (spontaneous alternation task). Guanosine did not reverted the impairment caused by MK-801 in the spontaneous alternation test, and when administered alone also presented an amnesic effect. The results are discussed based on the current hypothesis of locomotor activation induced by the psychoactive drugs studied. Further studies are necessary to evaluate if guanosine could have clinical utility for the treatment of schizophrenia.

Histamine H3 antagonist thioperamide dose-dependently enhances memory consolidation and reverses amnesia induced by dizocilpine or scopolamine in a one-trial inhibitory avoidance task in mice

In the literature, there is some evidence indicating that H3 histamine receptor antagonists, in particular thioperamide, can facilitate learning and memory retrieval in laboratory rodents. The present study aimed at verifying whether this also holds for memory consolidation, a phase of memory for which there is scarcity of convincing data on the effects of H3 receptor antagonists given systemically. To that end, memory consolidation was assessed in C57BL/6J mice using the one-trial step-through inhibitory avoidance task, the compounds being injected immediately after training (foot-shock) and performance measured 24 h later. More specifically, the following effects of thioperamide (1.25–20 mg/kg) were dose-dependently analysed: (1) its potential direct effects on memory consolidation; (2) its potential reversing effects on retrograde amnesia induced by the NMDA antagonist dizocilpine (MK-801, 0.5 mg/kg) and (3) its potential reversing effects on the well-known amnesia induced by the muscarinic antagonist scopolamine (0.25 mg/kg). We found that thioperamide exerted a dose-dependent facilitative effect on memory consolidation. Furthermore, the H3 receptor antagonist reversed scopolamine- and especially dizocilpine-induced amnesia. The results strongly support the view that the brain mechanisms of memory consolidation involve a functional interaction between the NMDA and the H3 sites.