Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that oversti...
Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.
Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.
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문제 정의
In this study, we identified behavioral effects of intraperitoneal NMDA administration on stereotypic nociceptive and repetitive behaviors. Most strikingly, we observed that intraperitoneal NMDA administration increased tail biting/licking behaviors along with general grooming.
제안 방법
As another measure of hyperalgesia or hypersensitivity effects of NMDA in nociceptive conditions, the writhing test was performed by counting the number of writhing behaviors (stretching, extension of hind legs, and contraction of the abdomen) recorded after acetic acid injection. Writhing frequency and number were increased by 0.
In order to determine whether the effect of NMDA is agedependent, we treated the mice at 3, 4, 5, 6, 7, and 8 weeks of age with 50 mg/kg NMDA. Tail biting/licking behaviors increased at 0.
The hot plate test was performed to evaluate possible hypersensitivity to heat after NMDA injection by measuring the latency to lick the paws and to jump from the hot surface. As a result, the latency of paw licking was decreased in the 75 mg/kg NMDA-exposed mice but not in the 50 mg/kg group (Fig.
대상 데이터
N-methyl-D-aspartate (NMDA, Cat No. M1360) was obtained from Tokyo Chemical Industry (Tokyo, Japan) and Glacial acetic acid (Cat No. 1005-4400) was purchased from Daejung Chemical (Seoul, Korea). NMDA and acetic acid were dissolved and diluted using normal saline (0.
We next examined the dose-dependency of NMDA effects on tail biting/licking behaviors. The doses of NMDA used in this study were 20, 30, 40, 50, and 75 mg/kg. The duration of tail biting/licking was similar to the vehicle group in the 20, 30, and 40 mg/kg NMDA groups.
데이터처리
Data were quantified and presented as mean ± standard error of the mean (SEM). Statistical analyses were conducted using one-way analysis of variance (ANOVA) followed by Newman-Keuls analysis. Two-way ANOVA was used to identify the interaction between two factors.
이론/모형
Intraperitoneal NMDA injection did not induce substantial BBB breakdown. BBB permeability was assessed using Evans blue assay. The number of animals per condition was follows: Vehicle group (n=3), NMDA 50 mg/kg group (n=3).
High concentrations of NMDA decreased the latency to paw licking or jumping in the hot plate test. Nociceptive heat sensitivity was measured using the hot plate test. (A) Latency to paw licking.
성능/효과
To unequivocally determine whether the observed stereotypic behaviors were accompanied by excitotoxicity and BBB breakdown, we performed Evans Blue BBB penetration analysis, and immunohistochemical assessments of BBB and neuronal integrity of thalamus and prefrontal cortex in vehicle or NMDA-exposed mice 1 h after NMDA injection. Although the positive control (stereotaxic surgical injury) showed a clear increase in Evans Blue penetration in the brain, the NMDA treated groups did not show a significant increase in Evans Blue penetration across all age groups examined in this study (4, 6 and 8 weeks), suggesting that extensive breakdown of the BBB was not elicited by our experimental conditions (Fig. 6). Similarly, immunohistochemical staining of NeuN, ZO-1, and peripheral IgG showed no differences between the NMDAtreated and the vehicle-treated groups, suggesting absence of both substantial BBB breakdown and excitotoxic cell death in the brain (Fig.
The 3, 4, and 5 weeks old NMDA-injected mice also showed higher tail biting/licking frequency than the vehicle group, while the 6, 7, and 8 week old groups showed no statistical differences when compared with their matched vehicle groups after 3 h (Fig. 3B). The correlation between tail biting/ licking behavior and age was inversely proportional to each other (Fig.
This study demonstrated that intraperitoneal NMDA administration increased self-grooming and nociceptive and repetitive behaviors, especially tail biting/licking behaviors, in juvenile mice. The effects were age- and dose-dependent and were unaccompanied by massive BBB breakdown and excitotoxic damage to neural tissue.
후속연구
In the present study, we found that systemic administration of NMDA induced stereotypic nociceptive/repetitive behaviors only in juvenile mice without inducing seizure- like behavior or massive damage to the BBB and brain. Whether the same or lower concentrations of NMDA (50 mg/ kg or less) modulates other psychiatric behaviors in juvenile rodents should be investigated further in future studies.
The effects were age- and dose-dependent and were unaccompanied by massive BBB breakdown and excitotoxic damage to neural tissue. While the results from the present study may add additional support for the widely accepted E/I imbalance hypothesis of neuropsychiatric disorders and demonstrate mechanistic usefulness of our approach as a model, careful characterizations by in depth behavioral profiling as well as investigation of the detailed molecular mechanism underlying the observed phenomena should be carried out going forward. In addition, a rigorous delineation of the human relevance of the observed behavioral manifestations is warranted.
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