- Open Access
Vitamin A depletion alters sensitivity of motor behavior to MK-801 in C57BL/6J mice
Behavioral and Brain Functions volume 6, Article number: 7 (2010)
Vitamin A and its derivatives (retinoids) are crucial for the development, maintenance and morphogenesis of the central nervous system (CNS). Although motor impairment has been reported in postnatal vitamin A depletion rodents, the effect of vitamin A depletion on homeostasis maintaining capability in response to external interference is not clear.
In the current study, we measured the effect of vitamin A depletion on motor ability and pain sensitivity under two different conditions: 1. prior to any injection and 2. after the injection of an N-methyl-D-aspartate (NMDA) receptor antagonist (MK-801).
Vitamin A depletion mice showed decreased body weight, enhanced locomotor activity, increased rearing and less tail flick latency. Vitamin A depletion also induced hypersensitivity of stereotypy, ataxia, rearing, and tail flick latency to MK-801, but hyposensitivity of locomotion to MK-801.
These findings suggest that vitamin A depletion affect broad basal behavior and disrupt homeostasis maintaining capability in response to glutamate perturbation. We provide a useful animal model for assessing the role of vitamin A depletion in regulating animal behavior, and for detecting how neurotransmitter pathways might be involved in vitamin A depletion related behavioral abnormalities.
Vitamin A and its derivatives (retinoids) play indispensable roles in the development, maintenance and morphogenesis of the central nervous system [1, 2]. By binding to their nuclear receptors(RARα, β, γ and RXRα, β, γ), retinoids induce or repress gene transcription by interacting with distinct promotor sequences in target genes . Retinoid receptors are widely distributed in the cortex, hippocampus, nucleus accumbens, and other brain tissues . During embryogenesis and early postnatal life, retinoic acid (the metabolic form of Vitamin A) facilitates nervous system development by guiding patterning and neuronal differentiation . In rodents, the control of neural patterning and differentiation are disrupted when retinoic acid concentrations are lowered . In mice, postnatal retinoic acid deficiency leads to significantly decreased neuronal differentiation within the granular cell layer of the dentate gyrus . In vitro, blockage of retinoic acid signaling prevents glial-induced neuronal differentiation . Retinoic acid also regulates neurite outgrowth . Retinoic acid clearly has an important role in regulating nervous system processes.
Previous studies suggest the involvement of retinoid signaling in regulating the transcription of neurotransmitter receptors. The dopamine D2 receptor promoter contains a functional retinoic acid response element and is regulated by retinoic acid [9, 10]. The dopamine D1 receptor is up-regulated by retinoids in the developing striatum . In addition, glutamate NMDA receptors [12–14] and non-NMDA receptors  are induced by retinoids in vitro. It is well known that the dysfunction of dopamine and glutamate systems participate in the pathophysiological processes of affective disorders, and also regulate animal behavior. Pharmacological interference has been widely used to clarify the influences of glutamate/dopamine systems on psychosis behavior in animals and humans. MK-801 is a potent and selective antagonist of NMDA receptors, which has been successfully used to study the role of glutamate signaling alteration in animal behavior. In experimental rodents, MK-801 induces psychosis symptoms including locomotor hyperactivity, stereotypy and deficits in spatial memory [16–18]. MK-801 also increases the extracellular dopamine level and regulates the dopamine D1, D2, D3, and D4 receptor gene expression in the hippocampus in a complex manner .
Although one previous study  reported the role of vitamin A depletion in regulating animal motor abilities, the question of how vitamin A depletion mice respond to glutamate perturbation is still not clear. An understanding of this response would be valuable in explaining the influence of vitamin A depletion on homeostasis maintaining capability and in determining how glutamate/dopamine systems might be involved in vitamin A depletion regulated behavioral abnormalities. We therefore considered it of interest to explore the effect of vitamin A depletion on both basal mice behavior and the sensitivity of mice behavior to MK-801 interference.
In the current study, we measured the effect of vitamin A depletion on broad behavioral paradigms (motor abilities and pain sensitivity) under two conditions: prior to any injection and after the injection of MK-801, and found that vitamin A depletion induced mild changes in body weight and basal behavior and that vitamin A depletion altered the sensitivity of motor abilities and nociception to glutamate perturbation in mice.
C57BL6 Jico inbred strain mice (Shanghai Laboratory Animal Center, Chinese Academy of Science, Shanghai, China; Warrant No. SCXK [Shanghai] 2007-0005) were housed at a constant temperature of 25 ± 2°C and 60% relatively humidity, on a 12 hour light-dark cycle (lights on at 7:00 h); food and water were available ad libitum. All experiments were conducted in accordance with the PRC national standards for laboratory animal quality and the Chinese guidelines for the care and use of laboratory animals.
For the generation of vitamin A depletion mice, successfully mated pregnant C57BL/6J mice were fed with a vitamin A free diet (D03102201) until the pups were weaned at the age of 3 weeks. Fifty six pups (male: female = 1:1) were selected randomly from 8 different litters, 28 of which (14 male, 14 female) were fed with a vitamin A free diet until they were sacrificed after the behavioral test. The other 28 pups (14 male, 14 female) were fed with a diet containing vitamin A 4,000 IU/kg (D06051001). The detailed composition of the vitamin A free diet (D03102201) and the normal diet (D06051001) are given in Additional file 1.
A separate group was housed and given vitamin A free food or normal food in the same manner as the previous group. Serums from 9-week mice were separated and stored at -70°C until analysis. The serums were analyzed for total retinol concentration using the high performance liquid chromatography (HPLC) method .
MK-801 was purchased from Sigma-Aldrich and dissolved in saline. As shown in a previous study , the injection of MK-801 (0.6 mg/kg, intraperitoneal [i.p.]) can induce hyperlocomotion, stereotypy and ataxia in mice. We selected this dose of MK-801 (0.6 mg/kg) to inject the mice and to observe subsequent behavior.
The offspring (vitamin A depletion group: male n = 14, female n = 14; control group: male n = 14, female n = 14) were transferred to the behavior testing facilities at 9 weeks of age and allowed 3-8 days to acclimatize before behavioral testing. The individual pups were randomly selected from 8 different litters and used as statistical units instead of litters for the analysis of behavioral results. This design will not overestimate any effects (type 1 error) (See previous study ).
Two rounds of behavioral testing were conducted for all animals. In the first round test (prior to MK-801 injection), locomotion, rearing and tail flick activity were tested in mice with the two different diets. One day after the first round test, the second round test was conducted. Mice from each of the two diet groups were injected only once with MK-801 (0.6 mg/kg, intraperitoneal [i.p.]) prior to the series of behavioral tests. The same behavioral paradigms as in the first round, as well as stereotypy and ataxia, were tested. All behavior testing occurred during daytime hours (from 8:00 to 17:00).
Locomotion and rearing
Locomotion measurement was assessed using automatic detection beam crossings in the Flex Field system (San Diego Instuments, San Diego, California, USA). Animals were placed in a 45 × 25 cm chamber (height 20 cm). Horizontal motion was detected by photobeams spaced at 5.0 cm lengthwise and 4.5 cm across, at a height of 2 cm. Rearing activity was measured by a second group of photodetectors mounted higher up, at 6 cm, at 2.5 cm intervals in the width direction. The recordings included the initial periods of adaptation to the novel environment. Locomotion and rearing were monitored for 3 hours. Data are presented as beam breaks per 5-min period unless otherwise indicated.
Stereotypy and ataxia
Stereotypic behavior represents amounts of repetitive behavior, usually at the expense of locomotion or other natural behavior . To measure stereotypic behavior, the animals in the measurement chambers were videotaped for 3 hour periods immediately after injection of MK-801 . Stereotypy measurement was made for the first 2 min out of each 5 min time segment. Behavior that could be observed in normal, drug-naive animals, such as grooming or gnawing, were not scored as stereotypy unless they lasted longer than 3 s. Each videotape had to be rated by two independent scorers who were blind to the experimental conditions. Scorers were trained as previously reported  so as to assure rating reliability. Meanwhile, during the videotape analysis we also scored ataxia behavior as previously reported .
Tail flick test
Thirty minutes after the locomotion test, we began the tail flick test using a Tail Flick Latency instrument (Stoelting, USA). A mouse was placed within a restraining tube with its tail protruding. The tail was placed on a level surface; a radiant heat was applied to the tail. Withdrawal latency was measured by the time taken for the mice to curl or flick the tail. The scores were based on the median of three tests, with 3-min intervals between each test.
Statistical analysis was performed using SPSS14.0 for Windows. Means are shown with error bars indicating the standard error mean (SEM). Multivariate ANOVA was used to analyze the data for locomotion, rearing, tail flick latency, stereotypy and ataxia prior to and after MK-801 injection, and diet and sex were selected as fixed factors. Univariate analysis of variance was used to analyze the data of weight using diet and sex as fixed factors. Data transformation (natural logarithm transformation) was used for the data for rearing and tail flick latency to meet the homogeneity of variance and normality. Independent sample t-tests were also used where necessary.
Serum levels of retinol
Serum retinol concentrations were significantly decreased in 9 week old vitamin A depletion mice compared to the control mice and were 32.5 ± 16.3 ng/ml in vitamin A depletion mice (n = 3) and 350.12 ± 53.48 ng/ml in control mice (n = 3) respectively. Values are shown as mean ± S.E.M; P < 0.01 (independent t-test).
Vitamin A depletion mice had significantly less body weight than the control mice at 9 weeks of age [F (1, 51) = 8.667, P = 0.005]. Male mice had significantly more body weight than female mice [F (1, 51) = 82.96, P < 0.001], but the interaction of diet and sex was not significant [F (1, 51) = 0.989, P > 0.05].
There was no main effect of diet [F (1, 47) = 2.172, P > 0.05] on accumulated horizontal beam breaks in the open field (Figure 1A). Vitamin A depletion mice showed no difference in locomotion (P > 0.05, t-test) compared to the control mice in the first 65 minutes of the test. However, vitamin A depletion mice showed significantly more cumulative locomotion from 65 to 180 minutes than the control mice (P < 0.001, t-test) (Figure 1B). After MK-801 injection, diet had a significant main effect [F (1, 46) = 12.28, P = 0.01] on locomotion. In particular, vitamin A depletion mice showed significantly less MK-801 induced hyperlocomotion (P < 0.05, t-test) (Figure 1C) than the control mice in the first 65 minutes. However, there was no significant difference in MK-801 induced hyperlocomotion between vitamin A depletion and control mice from 65 to 180 minutes (P > 0.05, t-test).
The natural logarithm of rearing data was used for data analysis in order to meet the homogeneity of variance and normality distribution. There was a significant main effect of diet [F (1, 47) = 18.63, P < 0.001] on rearing activities. In contrast to the stimulation of horizontal locomotion, rearing behavior has been shown to be significantly suppressed by MK-801 in normal mice . After MK-801 injection, diet also proved to have a significant main effect [F (1, 46) = 14.787, P < 0.001] on rearing activities. Vitamin A depletion mice showed significantly increased rearing activity (P < 0.001), but after MK-801 injection vitamin A depletion induced significantly reduced rearing activity (P < 0.001) (Figure 2), suggesting that vitamin A depletion may amplify the suppression effect of MK-801 on rearing.
The increase in stereotypy was induced after MK-801 injection (0.6 mg/kg, i.p.). There was a significant main effect of diet [F (1, 46) = 30.56, P < 0.001] on MK-801 induced stereotypy (Figure 3), indicating that vitamin A depletion induces hypersensitivity of stereotypy to MK-801.
ANOVA revealed a significant main effect of diet [F (1, 46) = 5.62, P = 0.022] on MK-801 induced ataxia (Figure 4) suggesting that vitamin A depletion results in hypersensitivity of ataxia to MK-801.
Tail flick latency
The natural logarithm of tail flick latency data was used for ANOVA analysis in order to meet the homogeneity of variance and normality distribution. There was a significant main effect of diet [F (1, 47) = 6.747, P = 0.012] and sex [F (1, 47) = 15.534, P < 0.001] on tail flick latency. After MK-801 injection, diet also had a significant main effect [F (1, 47) = 13.99, P = 0.001] on tail flick latency. Prior to MK-801 injection, vitamin A depletion significantly reduced tail flick latency (P = 0.012) whereas after MK-801 injection vitamin A depletion mice showed significantly increased tail flick latency (P = 0.001) (Figure 5).
The body weight and behavioral information of both male and female mice are shown in Additional file2.
In the present study vitamin A depletion mice displayed subtle and discrete changes in body weight and basal behavior. It was noticed that vitamin A depletion mice had significantly lower body weight than the control mice, suggesting the general health of mice was adversely influenced by vitamin A depletion. The major behavioral findings in vitamin A depletion mice are: (1) enhanced locomotor activity; (2) increased rearing activity and (3) reduced tail flick latency.
Locomotor activity was used to measure the response to a novel environment. Vitamin A depletion mice displayed enhanced locomotor activity from 65 to 180 minutes of the test but not in the first 65 minutes. This suggests that the effect of vitamin A depletion on locomotor activity is subtle and dependent upon the detection period. In a study by Carta et al, postnatal vitamin A deficiency rats showed a significant hyperlocomotion in the first 20 minutes of the test . This difference in time taken to show hyperlocomotion may be explained by the different animals used and the different methods used to generate the vitamin A depletion condition (we used vitamin A depletion mice, Carta et al used postnatal vitamin A deficiency rats). On the other hand, vitamin A depletion mice have also been shown to exhibit increased rearing activity, an exploratory behavior which reflects emotion and anxiety status . This abnormality of rearing activity in vitamin A depletion mice could reflect the impairment of the ability to adapt to the external environment. Tail flick latency reflects the ability to respond to thermal nociception. In the assessment of pain sensitivity, less tail flick latency was found in vitamin A depletion mice, indicating that they had increased thermal pain sensitivity. To our knowledge, there have been no reports on the relationship between retinoids and nociception. The peripheral nociceptors or sensory neurons in the spinal cord may be regulated by retinoids.
To measure the interaction between vitamin A depletion and glutamate signaling, we also assessed the sensitivity of behavioral phenotypes to external influences (MK-801 injection) in the vitamin A depletion mice. These mice showed altered sensitivity of several types of behavior to MK-801, including stereotypy, ataxia, rearing, locomotion and tail flick latency, suggesting that homeostasis maintaining capability in vitamin A depletion mice is reduced.
It is well known that the injection of a moderate dose (0.6 kmg/kg) of MK-801 can induce hyperlocomotion, stereotypy and ataxia in mice. In the present study, the vitamin A depletion mice showed hypersensitivity of stereotypy and ataxia to the NMDA receptor antagonist (MK-801), indicating that the neural circuits which might be disrupted by vitamin A depletion are involved in the glutamate pathway. Furthermore, after MK-801 injection, the vitamin A depletion mice had significantly less hyperlocomotion than the control mice in the first 65 minutes, but showed no difference in hyperlocomotion from 65 to 180 minutes. It has been reported that hyperlocomotion and stereotypy are competing behaviors  and that increased stereotypy could inhibit hyperlocomotion. Although the vitamin A depletion mice showed hyposensitivity of locomotion to MK-801, this finding warrants further investigation, perhaps by using a different dose of MK-801 to test dose effectiveness. It has been found that rats with a neonatal lesion of the amygdale showed hypersensitivity of locomotion to low dose phencyclidine (PCP) (<2 mg/kg), while showing hyposensitivity of locomotion to high dose PCP (>2 mg/kg) . Meanwhile, vitamin A depletion mice showed hypersensitivity of rearing activity to MK-801. MK-801 injection may induce severe ataxia in vitamin A depletion mice which could damage the motor ability of hind limbs and therefore decrease the rearing activity. In addition, vitamin A depletion mice showed significant increase in tail flick latency in response to MK-801, suggesting that vitamin A depletion exaggerates the vulnerability to external influences and might influence nociception sensitivity by regulating the pathway of peripheral NMDA receptor mediated responses to nociceptors [25, 26].
The altered sensitivities of stereotypy, ataxia, rearing, locomotion and tail flick latency to MK-801, suggest the involvement of vitamin A depletion in regulating balancing ability in response to external glutamate perturbation. One of our previous studies found that inhibiting retinoic acid synthesis in astrocytes could result in altered proteins related to glutamate metabolism . But until now, most of the evidence demonstrating the role of retinoids in regulating glutamate NMDA receptors (NR1, NR2) has come from in vitro studies . The involvement of vitamin A in regulating glutamate pathway-related molecules warrants further studies, including testing the effect of vitamin A on glutamate receptors and glutamate metabolic enzymes in vivo. The motor phenotypes in vitamin A depletion mice also indicate alteration in the dopamine systems [28–30]. In previous studies, vitamin A signaling has been shown to play an important role in regulating the dopamine system. It has been shown that (1) reduction of retinoic acid influences the development and specifying of motor neurons , (2) the D2 dopaminergic receptor gene contains a functional retinoic acid receptor response element (RARE) that is activated by a RARα-RXRγ heterodimer , (3) Nurr-1, another heterodimeric partner of RXRs is expressed in developing dopaminergic neurons  and MK-801 can indirectly activate dopamine systems in the brain . Therefore vitamin A depletion reduces the balancing abilities in response to external interference (MK-801 injection), probably by regulating the glutamate and dopamine pathway. Further studies of glutamate and dopamine pathway in different brain regions including hippocampus, cortex and striatum are required to clarify the mechanisms underlying altered sensitivity of stereotypy, ataxia, rearing, locomotion and tail flick latency to MK-801. Behavioral pharmacology studies using dopaminergic and glutamatergic agents are also valuable tools.
It has been found that behavioral changes in vitamin A depletion mice are related to psychosis symptoms. Enhanced locomotor ability and exaggerated sensitivity of stereotypy to MK-801 in vitamin A depletion mice are schizophrenia related symptoms [34, 35] and are found in schizophrenia animal models [36–39]. However, hyposensitivity of locomotion to MK-801 does not correspond with the schizophrenia phenotype in animals. Stereotypy is also found in patients with mental retardation and autism spectrum disorders. Interestingly, vitamin A depletion mice displayed normal locomotion initially (from 0 to 65 minutes) but increased locomotion gradually (from 65 to 180 minutes), which is somewhat relevant to delayed hyperactivity in children with attention-deficit/hyperactivity disorder (ADHD) . These findings add weight to the plausibility of the biological involvement of vitamin A cascade in the pathological processes of neuropsychiatric diseases.
The present study measured the response of vitamin A depletion mice and normal mice to the injection of single dose of MK-801 (0.6 mg/kg). The effect of MK-801 injection with different doses on motor behavior are deserved to be detected to reduce the possible bias caused by single dose injection. We proposed that glutamate system might be involved in vitamin A depletion related behavioral alteration. The detailed biochemical parameters should be measured to support that glutamate system is affected by vitamin A depletion, including the expression of glutamate receptors and the affinity for MK-801 on its receptors.
In summary, we found that vitamin A depletion increased basal motor behavior and pain sensitivity in the mice, as well as altering the sensitivity of motor ability and nociception to external influences (glutamate perturbation). These results may reflect reduced capability of vitamin A depletion mice to maintain homeostasis. Our findings also indicate that vitamin A depletion may induce behavioral alterations by disturbing the glutamate/dopamine pathway. The present study therefore indicates that vitamin A depletion mice are a valuable animal model for studying the role of vitamin A in regulating a range of behavior in mice, and for investigating the involvement of vitamin A signaling in important neurotransmitters pathways such as glutamate signaling.
Maden M: Retinoic acid in the development, regeneration and maintenance of the nervous system. Nat Rev Neurosci. 2007, 8: 755-65. 10.1038/nrn2212.
Lamantia AS: Forebrain induction, retinoic acid, and vulnerability to schizophrenia: insights from molecular and genetic analysis in developing mice. Biol Psychiatry. 1999, 46: 19-30. 10.1016/S0006-3223(99)00002-5.
Carta M, Stancampiano R, Tronci E, Collu M, Usiello A, Morelli M, Fadda F: Vitamin A deficiency induces motor impairments and striatal cholinergic dysfunction in rats. Neuroscience. 2006, 139: 1163-72. 10.1016/j.neuroscience.2006.01.027.
Krezel W, Kastner P, Chambon P: Differential expression of retinoid receptors in the adult mouse central nervous system. Neuroscience. 1999, 89: 1291-300. 10.1016/S0306-4522(98)00342-X.
McCaffery PJ, Adams J, Maden M, Rosa-Molinar E: Too much of a good thing: retinoic acid as an endogenous regulator of neural differentiation and exogenous teratogen. Eur J Neurosci. 2003, 18: 457-72. 10.1046/j.1460-9568.2003.02765.x.
Jacobs S, Lie DC, DeCicco KL, Shi Y, DeLuca LM, Gage FH, Evans RM: Retinoic acid is required early during adult neurogenesis in the dentate gyrus. Proc Natl Acad Sci USA. 2006, 103: 3902-7. 10.1073/pnas.0511294103.
Környei Z, Gócza E, Rühl R, Orsolits B, Vörös E, Szabó B, Vágovits B, Madarász E: Astroglia-derived retinoic acid is a key factor in glia-induced neurogenesis. FASEB J. 2007, 21: 2496-509. 10.1096/fj.06-7756com.
Clagett-Dame M, McNeill EM, Muley PD: Role of all-trans retinoic acid in neurite outgrowth and axonal elongation. J Neurobiol. 2006, 66: 739-56. 10.1002/neu.20241.
Samad TA, Krezel W, Chambon P, Borrelli E: Regulation of dopaminergic pathways by retinoids: activation of the D2 receptor promoter by members of the retinoic acid receptor-retinoid X receptor family. Proc Natl Acad Sci USA. 1997, 94: 14349-54. 10.1073/pnas.94.26.14349.
Farooqui SM: Induction of adenylate cyclase sensitive dopamine D2-receptors in retinoic acid induced differentiated human neuroblastoma SHSY-5Y cells. Life Sci. 1994, 55: 1887-93. 10.1016/0024-3205(94)00520-6.
Wang HF, Liu FC: Regulation of multiple dopamine signal transduction molecules by retinoids in the developing striatum. Neuroscience. 2005, 134: 97-105. 10.1016/j.neuroscience.2005.04.008.
Kulikov AV, Rzhaninova AA, Goldshtein DV, Boldyrev AA: Expression of NMDA receptors in multipotent stromal cells of human adipose tissue under conditions of retinoic acid-induced differentiation. Bull Exp Biol Med. 2007, 144: 626-9. 10.1007/s10517-007-0390-6.
Pizzi M, Boroni F, Bianchetti A, Moraitis C, Sarnico I, Benarese M, Goffi F, Valerio A, Spano P: Expression of functional NR1/NR2B-type NMDA receptors in neuronally differentiated SK-N-SH human cell line. Eur J Neurosci. 2002, 16: 2342-50. 10.1046/j.1460-9568.2002.02403.x.
Jelitai M, Schlett K, Varju P, Eisel U, Madarász E: Regulated appearance of NMDA receptor subunits and channel functions during in vitro neuronal differentiation. J Neurobiol. 2002, 51: 54-65. 10.1002/neu.10049.
Younkin DP, Tang CM, Hardy M, Reddy UR, Shi QY, Pleasure SJ, Lee VM, Pleasure D: Inducible expression of neuronal glutamate receptor channels in the NT2 human cell line. Proc Natl Acad Sci USA. 1993, 90: 2174-8. 10.1073/pnas.90.6.2174.
Tricklebank MD, Singh L, Oles RJ, Preston C, Iversen SD: The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol. 1989, 167: 127-35. 10.1016/0014-2999(89)90754-1.
Liljequist S, Ossowska K, Grabowska-Anden M, Anden NE: Effect of the NMDA receptor antagonist, MK-801, on locomotor activity and on the metabolism of dopamine in various brain areas of mice. Eur J Pharmacol. 1991, 195: 55-61. 10.1016/0014-2999(91)90381-Y.
Manahan-Vaughan D, von Haebler D, Winter C, Juckel G, Heinemann U: A single application of MK801 causes symptoms of acute psychosis, deficits in spatial memory, and impairment of synaptic plasticity in rats. Hippocampus. 2008, 18: 125-34. 10.1002/hipo.20367.
Healy DJ, Meador-Woodruff JH: Dopamine receptor gene expression in hippocampus is differentially regulated by the NMDA receptor antagonist MK-801. Eur J Pharmacol. 1996, 306: 257-64. 10.1016/0014-2999(96)00204-X.
Wu J, Zou H, Strong JA, Yu J, Zhou X, Xie Q, Zhao G Jin M, Yu L: Bimodal effects of MK-801 on locomotion and stereotypy in C57BL/6 mice. Psychopharmacology (Berl). 2005, 177: 256-63. 10.1007/s00213-004-1944-1.
Per Eriksson: Response to: Use of the Pup as the Statistical Unit in Developmental Neurotoxicity Studies: Overlooked Model or Poor Research Design?. Toxicological Sciences. 2008, 103: 411-413. 10.1093/toxsci/kfn037.
Qi C, Zou H, Zhang R, Zhao G, Jin M, Yu L: Age-related differential sensitivity to MK-801-induced locomotion and stereotypy in C57BL/6 mice. Eur J Pharmacol. 2008, 580: 161-8. 10.1016/j.ejphar.2007.07.071.
Lever C, Burton S, O'Keefe J: Rearing on hind legs, environmental novelty, and the hippocampal formation. Rev Neurosci. 2006, 17: 111-33.
Daenen EW, Wolterink G, Van Ree JM: Hyperresponsiveness to phencyclidine in animals lesioned in the amygdala on day 7 of life. Implications for an animal model of schizophrenia. Eur Neuropsychopharmacol. 2003, 13: 273-9. 10.1016/S0924-977X(03)00029-4.
Du J, Zhou S, Coggeshall RE, Carlton SM: N-methyl-D-aspartate-induced excitation and sensitization of normal and inflamed nociceptors. Neuroscience. 2003, 118: 547-62. 10.1016/S0306-4522(03)00009-5.
Jang JH, Kim DW, Sang Nam T, Se Paik K, Leem JW: Peripheral glutamate receptors contribute to mechanical hyperalgesia in a neuropathic pain model of the rat. Neuroscience. 2004, 128: 169-76. 10.1016/j.neuroscience.2004.06.040.
Zhang M, Wan C, Ji B, Zhang Z, Zhu H, Tian N, La Y, Huang K, Jiang L, He G, Gao L, Zhao X, Shi Y, Huang G, Feng G, He L: Proteome alteration of U251 human astrocytoma cell after inhibiting retinoic acid synthesis. Mol Cell Biochem. 2009, 323: 185-93. 10.1007/s11010-008-9978-z.
Chartoff EH, Marck BT, Matsumoto AM, Dorsa DM, Palmiter RD: Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation. Proc Natl Acad Sci USA. 2001, 98: 10451-6. 10.1073/pnas.181356498.
Delis F, Mitsacos A, Giompres P: Dopamine receptor and transporter levels are altered in the brain of Purkinje Cell Degeneration mutant mice. Neuroscience. 2004, 125: 255-68. 10.1016/j.neuroscience.2004.01.020.
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG: Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996, 379: 606-12. 10.1038/379606a0.
Ji SJ, Zhuang B, Falco C, Schneider A, Schuster-Gossler K, Gossler A, Sockanathan S: Mesodermal and neuronal retinoids regulate the induction and maintenance of limbinnervating spinal motor neurons. Dev Biol. 2006, 297: 249-61. 10.1016/j.ydbio.2006.05.015.
Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann TRH: Dopamine neuron agenesis in Nurr1-deficient mice. Science. 1997, 276: 248-50. 10.1126/science.276.5310.248.
Cook CD, Newman JL, Winfree JC, Beardsley PM: Modulation of the locomotor activating effects of the noncompetitive NMDA receptor antagonist MK801 by dopamine D2/3 receptor agonists in mice. Pharmacol Biochem Behav. 2004, 77: 309-18. 10.1016/j.pbb.2003.11.002.
Powell CM, Miyakawa T: Schizophrenia-relevant behavioral testing in rodent models: a uniquely human disorder?. Biol Psychiatry. 2006, 59: 1198-07. 10.1016/j.biopsych.2006.05.008.
Bubeníková-Valesová V, Horácek J, Vrajová M, Höschl C: Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev. 2008, 32: 1014-23. 10.1016/j.neubiorev.2008.03.012.
Kesby JP, Burne TH, McGrath JJ, Eyles DW: Developmental vitamin D deficiency alters MK 801-induced hyperlocomotion in the adult rat: An animal model of schizophrenia. Biol Psychiatry. 2006, 60: 591-6. 10.1016/j.biopsych.2006.02.033.
Al-Amin HA, Weinberger DR, Lipska BK: Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus. Behav Pharmacol. 2000, 11: 269-78.
Mohn AR, Gainetdinov RR, Caron MG, Koller BH: Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell. 1999, 98: 427-436. 10.1016/S0092-8674(00)81972-8.
Rojas P, Joodmardi E, Hong Y, Perlmann T, Ogren SO: Adult mice with reduced Nurr1 expression: an animal model for schizophrenia. Mol Psychiatry. 2007, 12: 756-66. 10.1038/sj.mp.4001993.
Sagvolden T, Russell VA, Aase H, Johansen EB, Farshbaf M: Rodent models of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005, 57: 1239-1247. 10.1016/j.biopsych.2005.02.002.
We thank Dr. Yujuan La for her assistance and advice of generating vitamin A depletion mice and for HPLC work. This work was supported by the 973 Program (2006CB910600, 2010CB529600, 2007CB914703, 2007CB947300), the 863 Program 2006AA02A407, the Shanghai Municipal Commission of Science and Technology Program (09DJ1400601, 07DZ22917), the National Key Project for Investigational New Drug 2008ZX09312-003, the National Natural Science Foundation of China (No. 30700203), and the Shanghai Leading Academic Discipline Project (B205).
The authors declare that they have no competing interests.
ZM carried out HPLC experiments, data analysis and interpretation. ZBH, ZH, SJW and ZH conducted the behavioral experiments. ZZ assisted in data analysis. YL and JML revised the manuscript and provided suggestions. FGY provided experimental drugs. WCL and HL directed the overall project and coordinated data collection. All authors have read and approved the final manuscript.
Electronic supplementary material
Additional file 2: Body weight and behavioral information in VAD and control mice. Behavioral results in VAD and control mice were showed, including locomotion, rearing, tail flick latency, stereotype and ataxia with and without MK-801 injection. In addition, the body weight of VAD and control mice were also showed. (DOC 47 KB)
About this article
Cite this article
Zhang, M., Ji, B., Zou, H. et al. Vitamin A depletion alters sensitivity of motor behavior to MK-801 in C57BL/6J mice. Behav Brain Funct 6, 7 (2010) doi:10.1186/1744-9081-6-7
- Autism Spectrum Disorder
- Retinoic Acid
- Motor Ability
- Tail Flick