Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-d-aspartate non-competitive channel blocker MK801

doi:10.1016/S0166-4328(05)80249-9

Behavioural Brain Research

Volume 47, Issue 1, 15 March 1992, Pages 23-33

https://doi.org/10.1016/S0166-4328(05)80249-9 Get rights and content

Three doses of MK801 (0.05 mg/kg 0.3 mg/kg and 1.0 mg/kg) were given systemically to adult male rats, which were then tested on a battery of previously learned, reactive and spontaneous behaviors. Hyperactivity, hyper-reactivity, reductions in rearing behavior and deficits in tongue extension were found at the 0.05 mg/kg dose. Similar, but more severe results were found at the 0.3 mg/kg dose, with the addition of difficulties in climbing, balancing on a beam, and abnormalities in orienting to tactile stimuli. A number of tasks could not be performed at the 1.0 mg/kg dose including tongue extension, orienting, balancing on a beam, and climbing. Additionally, abnormal postures, gaits, and swimming behaviors were observed at this dose. These results characterize the behavioral effects of MK801 as a syndrome of hyperactivity, hyper-reactivity, and sensorimotor deficits. Evidence of this syndrome was present at all three doses, including the 0.05 mg/kg dose, which previously has been claimed to induce deficits similar to hippocampal lesions. Learning literature employing MK801 is discussed in the context of the behavioral deficits found in this study.

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Sex-specific behavioral impairments produced by neonatal exposure to MK-801 are partially reversed by adolescent CDPPB treatment
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Psychomimetic behaviors manifest in adult rodents long after neonatal exposure to the noncompetitive NMDA receptor antagonist MK-801. In the present study, we used this neurodevelopmental model of schizophrenia to evaluate the therapeutic potential of positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) during adolescence. To this end, we randomly assigned male and female C57BL6 mouse littermates to one of three treatment groups: (i) neonatal and adolescent saline, (ii) neonatal MK-801 (0.25 mg/kg) and adolescent saline, and (iii) neonatal MK-801 and adolescent CDPPB (10 mg/kg), a positive allosteric modulator of mGluR5. When animals reached adulthood, a wide range of behavioral tests were conducted including sucrose preference, anxiety assessment in the elevated plus maze, and a series of food-reinforced operant procedures meant to assess motor activity, motivation, learning, and attention. Neonatal MK-801 exposure produced profound motor hyperactivity in both sexes and attenuated sucrose preference in males, effects that were reversed by CDPPB. MK-801 produced other deficits such as impaired set shifting or response inhibition deficits that were not reversed by CDPPB. Overall, female mice were more susceptible to MK-801's behavioral effects than males. These findings further support the use of neonatal MK-801 exposure as an animal model of schizophrenia and suggest that CDPPB can reverse the neurodevelopmental progression of some schizophrenia-like behaviors.
Neuro-behavioral effects after systemic administration of MK-801 and disinhibition of the anterior thalamic nucleus in rats: Potential relevance in schizophrenia
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Non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonists have been suggested to evoke psychotomimetic-like behaviors by selectively targeting GABAergic elements in cortical and thalamic circuits. In previous studies, we had reported the involvement of the reticular and anterior thalamic nuclei (ATN) in the MK-801-evoked hyperactivity and other motor alterations. Consistent with the possibility that these responses were mediated by thalamic disinhibition, we examined the participation of cortical and hippocampal areas innervated by ATN in the responses elicited by the systemic administration of MK-801 (0.2 mg/kg) and compared them to the effects produced by the microinjection of a subconvulsive dose of bicuculline (GABA_A receptor antagonist) in the ATN. We used the expression of Fos related antigen 2 (Fra-2) as a neuronal activity marker in the ATN and its projection areas such as hippocampus (HPC), retrosplenial cortex (RS), entorhinal cortex (EC) and medial prefrontal cortex (mPFC). Dorsal (caudate-putamen, CPu) and ventral striatum (nucleus accumbens, core and shell, NAc,co and NAc,sh) were also studied.
Behavioral and brain activation results suggest a partial overlap after the effect of MK-801 administration and ATN disinhibition. MK-801 and ATN disinhibition increases locomotor activity and disorganized movements, while ATN disinhibition also reduces rearing behavior. A significant increase in Fra-2 immunoreactivity (Fra-2-IR) in the ATN, mPFC (prelimbic area, PrL) and NAc,sh was observed after MK-801, while a different pattern of Fra-2-IR was detected following ATN disinhibition (e.g., increase in DG and NAc,sh, and decrease in PrL cortex). Overall, our data may contribute to the understanding of dysfunctional neural circuits involved in schizophrenia.
Psychotomimetic effects of different doses of MK-801 and the underlying mechanisms in a selective memory impairment model
2017, Behavioural Brain Research
Citation Excerpt :
However, a variety of psychotomimetic effects, including hyperlocomotion, sensorimotor deficits and affection changes were also observed [15,27]. These non-cognitive side effects have long been recognized to confound the performance of animals in memory tests, and may mask real cognitive effects in studies [25,26,31]. Therefore, it is crucial to disassociate the memory impairments from those side effects.
Although N-methyl-d-aspartate receptor antagonists-induced hypoglutamate rodent models are the most well-established models for preclinical studies of schizophrenia-related deficits, they also evoke a wide spectrum of psychotomimetic side effects. It is significant to increase the specificity of hypoglutamate rodent models. In this study, the recognition memory was evaluated in rats by object recognition test (ORT), sensorimotor gating was evaluated by prepulse inhibition of the startle reflex (PPI), and locomotor activity was measured using open field test. High-performance liquid chromatography was used to measure neurotransmitters content in the medial prefrontal cortex (mPFC) and thalamus (THA). Total Akt and phospho-Akt protein was measured by Western blots. Results showed that 0.3 mg/kg of MK-801 was most effective in inducing locomotion. 0.3 mg/kg of MK-801 was most effective in decreasing PPI. 0.03 mg/kg of MK-801 was most effective in decreasing object memory while not affecting exploration manners in the training session. 0.03 mg/kg of MK-801 significantly increased HVA and Glu content in the mPFC. 0.1 mg/kg of MK-801 significantly decreased GABA content in the THA. 0.03 mg/kg of MK-801 significantly decreased Akt phosphorylation in the mPFC, which was related to the ORT index. In conclusion, a dose of 0.03 mg/kg MK-801 can establish a “pure” memory impairment model without contaminations of sensorimotor gating and locomotor activity. MK-801-induced cognitive deficits is associated with increased DA metabolites and glutamate content in the mPFC and decreased GABA content in the THA as well as decrease in Akt phosphorylation in the mPFC.
Effects of the GluN2B-NMDA receptor antagonist Ro 25-6981 on two types of behavioral flexibility in rats
2017, Behavioural Brain Research
Citation Excerpt :
These are important observations, since they suggest a highly selective role of GluN2B subunits in spatial, navigational behavior. Further, these data indicate that drug treatment did not induce non-specific sensory-motor deficits or other behavioral side-effects that are often observed with NMDAR antagonists and that can lead to performance impairments in tasks assessing learning and memory functions in rodents [14,15]. The results reported here confirm previous work demonstrating reversal learning deficits in spatial and operant tasks following GluN2B disruptions.
Recent evidence has implicated N-methyl-d-aspartate receptors (NMDARs) in several aspects of learning and behavioral flexibility in rodents. Here, we examined the effects of treatment with Ro 25-6981, a selective antagonist of NMDARs containing GluN2B subunits, on two types of behavioral flexibility in rats, spatial reversal learning and set-shifting (spatial vs. motor strategy). To examine spatial reversal learning, rats were trained to swim to a hidden platform in a water maze over four days. On the following day, the platform was moved to a new location in the maze. Administration of Ro 25-6981 (10 mg/kg) selectively impaired the early phase of reversal learning, but all rats learned to navigate to the new platform location over 12 trials. To examine set-shifting, independent groups of rats were trained to either swim to a fixed location (spatial strategy) or use a motor response (e.g., “turn left”; motor strategy) to find a hidden escape platform in a cross-shaped water maze apparatus; after task acquisition, rats were trained on the second, novel strategy (set-shift) following treatment with either Ro 25-6981 (10 mg/kg) or saline. Administration of Ro 25-6981 had no effect on the ability of rats to perform the set-shift and use the new strategy to locate the escape platform. These results suggest that, in rats, spatial reversal learning, but not set-shifting, is sensitive to Ro-25-6981 treatment. Thus, NMDARs-GluN2B signaling may play a selective role in some forms of behavioral plasticity, particularly for situations involving the updating of information in the spatial domain.
Pre-training in a radial arm maze abolished anxiety and impaired habituation in C57BL6/J mice treated with dizocilpine
2016, Physiology and Behavior
Citation Excerpt :
Hence, it appears that NMDA receptor-dependent synaptic plasticity is not necessary in all forms of learning. MK-801 at 1 and 0.05 mg/kg have been reported to induce alterations in both sensory processing and motor performance that interfere with learning [3,37,44,108]. In the present study, these sensory-motor disturbances were not apparent though our data revealed that pre-trained mice were hyperactive.
Familiarity can imply a reduction of fear and anxiety, which may render learning and memory performance insensitive to NMDA receptor antagonism. Our previous study indicates that MK-801 (dizocilpine), NMDA antagonist, increased anxiety and prevented the acquisition of a spatial memory task. Here, we examined whether MK-801 will produce anxiety in mice that were familiar with the test environment.
Male C57BL/6J mice were exposed, one session a day for 7 days, to a 3D maze, which consisted of nine arms attached to upward inclined bridges radiating from a nonagonal platform. In this maze, high anxiety mice avoid the arms in the first sessions. One group of mice received saline (SAL) while a second group received MK-801 (MKD1), both on day one. A third group received saline in the first 3 sessions, and MK 801 in subsequent sessions (MKD4). Saline and MK-801 (0.1 mg/kg) were administered intraperitoneally 30 min before the test.
MKD4 mice demonstrated an increase in bridge and arm visits, and reached arm/bridge entries ratio close to 1 in session 5. SAL mice also crossed frequently onto the arms, and reached a comparable ratio, but this was achieved with a lower number of arm visits. MKD1 mice demonstrated a reduced number of arm visits in each session compared to SAL and MKD4 mice.
Dizocilpine produced anxiety in mice treated from day 1 of the test, but not in those treated from day 4. It also impaired habituation in animals familiar with the test environment; it produced sustained non-habituating hyperactivity.
Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment
2016, Behavioural Brain Research
NMDA GluN2B (NR2B) subtype selective antagonists are currently in clinical development for a variety of indications, including major depression. We previously reported the selective NMDA GluN2B antagonists Ro 63–1908 and traxoprodil, increase premature responding in a 5-choice serial reaction time task (5-CSRTT) suggesting an effect on impulsive action. The present studies extend these investigations to a Go-NoGo and delay discounting task, and the 5-CSRTT under test conditions of both regular (5 s) and short (2–5 s) multiple ITI (Intertrial interval). Dizocilpine was included for comparison. Both Ro 63–1908 (0.1–1 mg/kg SC) and traxoprodil (0.3–3 mg/kg SC) increased premature and perseverative responses in both 5-CSRT tasks and improved attention when tested under a short ITI test condition. Ro 63–1908 but not traxoprodil increased motor impulsivity (false alarms) in a Go-NoGo task. Dizocilpine (0.01–0.06 mg/kg SC) affected both measures of motor impulsivity and marginally improved attention. In a delay discounting test of impulsive choice, both dizocilpine and Ro 63–1908 decreased impulsive choice (increased choice for the larger, delayed reward), while traxoprodil showed a similar trend. Motor stimulant effects were evident following Ro 63–1908, but not traxoprodil treatment − although no signs of motor stereotypy characteristic of dizocilpine (>0.1 mg/kg) were noted. The findings of both NMDA GluN2B antagonists affecting measures of impulsive action and compulsive behavior may underpin emerging evidence to suggest glutamate signaling through the NMDA GluN2B receptor plays an important role in behavioural flexibility. The profiles between Ro 63–1908 and traxoprodil were not identical, perhaps suggesting differences between members of this drug class.

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Hyperactivity, hyper-reactivity, and sensorimotor deficits induced by low doses of the N-methyl-d-aspartate non-competitive channel blocker MK801

Brain Res.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Neurosci. Lett.

Trends. Neurosci.

Neuroscience

Physiol. Behav.

Pharmacol. Biochem. Behav.

Physiol. Behav.

Neuropsychologia

Eur. J. Pharm.

Behav. Brain Res.

Physiol. Behav.

Neuropharmacology

MK-801 and combined propranol with MK-801 produce motor deficits but do not impair learning in the water task

Effects of the NMDA receptor antagonist MK-801 on LTP in freely behaving rats

Neurosci. Abstr.

Excitatory amino acids in synaptic transmission in the schaffer collateral-commissural pathway of the rat hippocampus

J. Physiol.

Exploration-dependent enhancement of synaptic responses in rat fascia dentata is blocked by MK801

Neurosci. Abstr.