Monosodium glutamate (MSG) treatment of neonatal rodents leads to degeneration of theneurons in the arcuate nucleus, inner retinallayers and various other brain areas. It alsocauses various changes in the motor activity, sensory performance and learning abilities. Wehave previously shown that MSG treatmentdelays the appearance of some reflexes dur-ing neurobehavioral development and leads to temporary changes in reflex performance and motor coordination. Investigation of novelty-seeking behavior is of growing importance for its relationship with sensitivity to psychomotor stimulants. Perinatal administration of numer-ous toxic agents has been shown to influencenovelty-seeking behavior in rats, but little is known about the influence of neonatal MSGtreatment on the novelty-seeking behavior. The aim of the present study was to compare chang-es in locomotor, spontaneous exploratory andnovelty-seeking behavior in periadolescent ratsneonatally treated with MSG. Newborn ratswere treated with 4 mg/g MSG subcutaneously on postnatal days 1, 3, 5, 7 and 9. Open-field behavior was tested at 2, 3, 4, 6 and 8 weeks of age. We found that MSG administration led to only temporary increases in locomotor behavior, which was more pronounced during the first few postnatal weeks, followed by a subtle hypoactiv-

ity at 2 months of age. Novelty-seeking was test-ed in four 5-min trials at 3 weeks of age. Trial 1 was in an empty open-field, two identical objectswere placed in the arena during trial 2 and 3, and one of them was replaced to a novel object during trial 4. We found that the behavioral pat-tern of MSG-treated rats was the opposite in all tested signs in the novelty exploration test com-pared to control pups. In summary, our present study shows that neonatal MSG treatment leads to early temporary changes in the locomotor activity followed by hypoactivity at 2 monthsof age. Furthermore, MSG-treated rats show amarkedly disturbed novelty-seeking behavior represented by altered activity when subjectedto a novel object.

Keywords: MSG; Neonatal; Rat; Exploratory behavior

INTRODUCTION

Hundreds of compounds are known to exert neuro-toxic effects when given in relatively small amountsor in abnormally high concentrations (Kostrzewa,1999; Segura-Aguilar and Kostrzewa, 2004; 2006). When administered during the perinatal period, anumber of them are known to produce a delay or

F.P. Graham Publishing Co.

Changes in Open-Field Activity and Novelty-SeekingBehavior in Periadolescent Rats Neonatally Treated with Monosodium GlutamateP. KISSa, D. HAUSERa, A. TAMASa, A. LUBICSa, B. RACZb, Z. HORVATHa, J. FARKASa, F. ZIMMERMANNa, A. STEPIENa, I. LENGVARIa and D. REGLODIa,*

Department of aAnatomy and a bDepartment of Surgical Research and Techniques, University of Pecs,b

Medical Faculty, Hungary. dora.reglodi@aok.pte.hu

(Submitted 27 April 2007; Revised 5 July 2007; In final form 30 July 2007)

*Corresponding author: Tel.: +36/30/2849017; FAX: +36/72/536393; E-mail: dora.reglodi@aok.pte.hu

ISSN 1029 8428 print/ ISSN 1476-3524 online. © 2007 FP Graham Publishing Co., www.NeurotoxicityResearch.com

Neurotoxicity Research, 2007, VOL. 12(2). pp. 85-93

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long-lasting impairment in neurobehavioral devel-opment, motor and cognitive functioning in new-born rats (Harry, 1998; Koehl et al., 2001; Beninger et al., 2002; Reddy et al., 2002; Archer et al., 2002;2003; Kostrzewa et al., 2003; Palomo et al., 2003).Glutamate, the major excitatory neurotransmitter in the brain, is also categorized as an excitotoxin (Segura-Aguilar and Kostrzewa, 2004). Monosodium glutamate (MSG) is used as a food

additive, which causes only minor alterations in adults. However, administration of MSG to neonatalrodents brings about several profound changes. It leads to degeneration of the neurons in the arcuatenucleus, inner retinal layers and various other brain areas (Kubo et al., 1993; Ishikawa et al., 1997;Beas-Zarate et al., 2002; Tamas et al., 2004; Babaiet al., 2005; 2006), along with endocrinological, neurochemical and circadian alterations (Dawsonand Lorden, 1981; Miyabo et al., 1985; Frieder and Grimm, 1987; Mistlberger and Antle, 1999; Urena-Guerrero et al., 2003; Kim et al., 2005). The neurotoxicity of MSG is also reflected in various changes in the motor activity, sensory performance and learning ability (Iwata et al., 1979; Saari et al., 1990; Fisher et al., 1991; Dubovicky et al., 1997). We have previously shown that MSG treatment delays the appearance of some reflexes during neu-robehavioral development and leads to temporary changes in reflex performance and motor coordina-tion (Kiss et al., 2005; 2006). Locomotor activity has been reported both to be increased (Araujo and Mayer, 1973; Katz, 1983; Klingberg et al., 1987; Saari et al., 1990; Dubovickyet al., 1997) or decreased (Pizzi and Barnhart, 1976; Poon and Cameron, 1978; Iwata et al., 1979; Seress,1982; Hlinak et al., 2005) following neonatal MSG treatment. It has also been shown that spontaneousactivity does not differ in MSG-treated rats fromcontrols, but apomorphine-challenged motor activ-ity decreases after MSG-treatment (Klingberg et al., 1987; Ishikawa et al., 1997; Ali et al., 2000; Sanchis-Segura and Aragon, 2002). The investigation of novelty-seeking behavior is of growing importance for its relationship with sensitivity to psychomotor stimulants (Kabbaj et al., 2000; Stansfield et al., 2004; Zheng et al., 2004).Early adolescent period is an especially sensitiveperiod to test novelty exploration (Stansfield et al., 2004). Perinatal administration of numerous drugs,

including toxic agents, has been shown to influencenovelty-seeking behavior in rats (Ledig et al., 1998;Adriani et al., 2003; Heyser et al., 2004). Little is known about the influence of neonatal MSG treat-ment on the novelty-seeking behavior. The aim of the present study was to compare changes inlocomotor, spontaneous exploratory and novelty-seeking behaviors in periadolescent rats neonatallytreated with MSG.

MATERIALS AND METHODS

AnimalsLitters of Wistar rats (n=10±2) with mixed sexes were used. Animals were maintained under 12-hour light/dark cycle with free access to food and water.Pups were weaned after 3 weeks of age. Animalhousing, care and application of experimental pro-cedures were in accordance with institutional guide-lines under approved protocols (No: BA02/2000-20/2006, University of Pecs).

MSG TreatmentRat pups received 4 mg/g MSG subcutaneously (n=40), dissolved in physiological saline on post-natal days 1, 3, 5, 7 and 9, similarly to previous descriptions (Klingberg et al., 1987; Kiss et al.,2006). Control animals received only physiologicalsaline on the same days (n=26). Control and MSG-treated rats were randomly distributed among thedams: each dam contained both MSG-treated and control pups. Weight of the animals was recorded weekly.

Open-Field ActivityGroups of MSG-treated (n=14) and control (n=12)animals were observed for locomotor behavior inan open-field at 2, 3, 4, 6 and 8 weeks of age as previously described (Reglodi et al., 2003; Lubicset al., 2005). After acclimatization to the environ-ment, pups were placed in an open-field consistingof a 42x42 cm box with 21 cm high walls around. The floor was divided into 8x8 areas. Subjects wereplaced individually in the center, always facing thesame direction, and were video-recorded for 5 min-utes. Recordings were evaluated in a blinded fash-ion. The following parameters of locomotor activity were measured: ambulation time (time spent withforward movements of the limbs), number of fields

NEONATAL MSG & ALTERED BEHAVIORS IN RATS 87

crossed, distance traveled, head lifting, rearing and grooming behavior. Speed was calculated from the ambulatory time and the total traveled distance.Habituation index was calculated as a percentage of areas crossed during the first 90 seconds in relationto the total crossed fields. The time spent in the first zone next to the wall or in one of the four cornerswas also recorded.

Novelty-Seeking BehaviorObject exploration was conducted in separate groups of animals. MSG treatment was the same as described above (n=12), control animals received only saline treatment (n=12). Testing consisted of four 5-min trials at 3 weeks of age, according to previous descriptions (Heyser et al., 2004). Therewas a 3-min interval between the trials and the arena was carefully cleaned between sessions. The field was a 42x42 cm box with 21 cm high walls around and with a floor divided into 8x8 areas. There wereno objects in the field during trial 1, which served as a familiarization period to the novel environment.In trial 2, two identical pink glasses filled with sand with white covers were placed in the open-field. The objects were round, 13 cm in height and 9 cm in diameter. These objects were of sufficient height and weight so that they could not be climbed or moved. The objects were positioned equidistant from the walls and from each other. The same twoobjects remained in the open-field during trial 3.In trial 4, one of the objects (familiar object) was replaced with a novel object, which was a quad-rangular white plastic container of 10x10 cm baseand 22 cm height, with a blue top. The behavior of each animal was video-recorded for 5 minutes,and behaviors were evaluated later in a blinded fashion. Total ambulation time, number of fieldscrossed, time spent in the center and in the peripherywere recorded during each trial. Central area was regarded as the fields contacting the object and their neighboring ones. During trial 4, the time spent inthe proximity of the familiar and the novel objects were recorded separately. Habituation index wascalculated as a percentage of areas crossed duringthe first 90 seconds in relation to the total crossed fields.

Statistical AnalysisAll values are given as mean ± standard error of

the mean (SEM). Comparison between control and MSG-treated groups was done with ANOVA test followed by Dunn`s posthoc analysis. Novelty-seeking behavior was further analyzed with split-plot ANOVA.

RESULTS

Open-Field ActivityDuring the treatments, 2 control and 14 MSG-treated rats died, mainly during the first week. Dataof animals that died were not included in the final evaluations. Similarly to our earlier findings and those by others (Klingberg et al., 1987; Kiss et al., 2005) we found no significant difference in anytest between female and male rats, the results given below are mean results of both gender groups. Results of the open-field activity are summarized in Table I. Weights of MSG-treated were signifi-cantly less, throughout the observation period, than those of control pups in spite of similar initialweights. Ambulation time, the number of fieldscrossed, and the speed calculated from the total traveled distance and ambulation time are all signsof the locomotor activity. In general, MSG-treated rats were more active during the first 3 postnatalweeks. A markedly increased activity was observed on week 2, when control animals moved very littlewhile the time spent with ambulation and the cov-ered area showed a more than two-fold increase in MSG-treated animals compared to those observed in control pups. Since there was no difference inthe speed of movement between the two groups, this increase in the traveled distance could not be attributed to increased speed. At 3 weeks of age, the locomotor activity of all animals increased mark-edly. The speed of the MSG-treated pups increased significantly when compared to control animalsand this led to significantly larger explored areas in spite of the similar times spent with ambulation.At 4 weeks of age, most differences disappeared:MSG-treated pups became slower, leading to no significant differences in the covered area between MSG-treated and control rats. At 6 weeks of age,there was no difference between the two groups,while at 8 weeks of age, MSG-treated pups moved significantly less than their control littermates. No such differences could be observed in the vertical activity of the animals: the number of headlifts and

P. KISS et al.88

rearings were not significantly different during most of the observation period, the number of headliftswas lower in MSG-treated rats only at 3 weeks of age, which was compensated with a slightly higher number of rearings. No differences were observed in the grooming activity or in the habituation index. The time spent at walls (thigmotaxis) was higher inMSG-treated pups at 2 weeks of age, although this difference was not statistically significant due to the high number of control animals that did not moveaway from the central starting position. At following weeks, MSG-treated pups spent significantly less time at the walls.

Novelty-seeking BehaviorResults of the novelty-seeking behavior are sum-marized in Figures 1 and 2. Only results of trials2-4 are shown, the first trial served as acclimatiza-tion period. MSG treatment had a highly significant overall effect on locomotion (F=(( 15.39, P=0.0003for ambulation time and F=7.534, P=0.009 for

crossed fields). During trials 2 and 3, when thesame objects were present in the arena, there wasno difference between the ambulation times within the same groups, but MSG-treated rats showed significant hyperactivity compared to the control group (FIG. 1A). The activity of control rats sig-nificantly increased during trial 4, when the novelobject was introduced. MSG-treated rats showed an opposite behavior: activity was reduced during trial 4. The same pattern was observed when the number of fields was evaluated: in contrast to control rats, MSG-treated rats showed an increased exploration during trials 2 and 3, but it decreased during trial 4(FIG. 1B). The overall effect of MSG on habituation was also significant (F=(( 9.178, P=0.0044). Controlrats showed no change in the habituation index during trials 2 and 3, and rats were more activeduring the first 90 seconds of the trials (FIG. 1C).Habituation significantly decreased during trial 4,meaning that rats were almost equally active during the first and second halves of the observation time

NEONATAL MSG & ALTERED BEHAVIORS IN RATS 89

FIGURE 1 Ambulatory activity (A), total number of crossed fields (B), habituation index (C) and total groomingactivity (D) in the novelty-seeking test of control and MSG-treated rats during trials 2-4. Habituation index was cal-culated as a percentage of areas crossed during the first 90 seconds in relation to the total crossed fields. Results are given as mean ± SEM. *P <0.05, **P P <0.01 compared to control group, P #P# <0.05, P ##P# <0.01 compared to the previousPtrial within the same group.

FIGURE 2 Time spent in the central and peripheral zones of the arena during the novelty-seeking test in trials 2-4in control (A) and MSG-treated (B) rats, and the time spent in the proximity of the familiar and novel objects during trial 4 in control and MSG-treated rats (C). Results are given as mean ± SEM. *P <0.05, ***P P <0.001 compared toPcontrol group, #P# <0.05 compared to the previous trial within the same group.P

P. KISS et al.90

when exposed to the novel object. MSG-treated rats showed an opposite pattern of habituation: it decreased during trial 3, and increased during trial 4 (FIG. 1C). Although the overall effect of MSG treatment on grooming behavior was not significant (F=0.9591, P=0.33), the patterns during the trials were opposite in control and MSG-treated animals (FIG. 1D). Control rats spent more time with groom-ing during trial 3 when the arena contained no nov-elty, and spent less time with grooming during trial 4 when the novel object was present. MSG-treated rats had significantly decreased grooming behavior during trial 3, while it increased during trial 4. Comparison of the times spent in the center (in proximity with the objects) and in the periphery shows significant overall effect of MSG treatment (F=8.003, P=0.0073). All animals spent signifi-cantly more time in the periphery than in the center during trial 2 (FIG. 2A, B). The ratio between the times spent in the center and periphery did not change during trial 3 in control rats, but a significant increase in the time spent in the center was observed during trial 4 (FIG. 2A). During trial 4, there was no longer a significant difference between central and peripheral times, so animals spent significantly more time in the proximity of the objects when the novel object was introduced, compared to trial 3. In MSG-treated rats, the difference between the central and peripheral times disappeared already during trial 3, when the same two objects were present as during trial 2 (FIG. 2B). Calculating the times spent in the proximity of the novel and familiar objects during trial 4 shows that control rats spent signifi-cantly more time exploring the novel object, while MSG-treated rats spent less time in the proximity of the novel object (FIG. 2C).

DISCUSSION

In the present study we showed that neonatal MSG treatment caused a temporary hyperactivity dur-ing the early postnatal period followed by a slight hypoactivity at 8 weeks of age. MSG treatment also reduced the time of thigmotaxis after week 3. Novelty-seeking behavior was significantly altered after MSG treatment: treated animals showed a nov-elty-seeking pattern opposite to control rats. As far as motor activity is concerned, results obtained by different investigators vary: both

hypoactivity (Pizzi and Barnhart, 1976; Poon and Cameron, 1978; Iwata et al., 1979; Seress, 1982; Hlinak et al., 2005) and hyperactivity (Araujo and Mayer, 1973; Katz, 1983; Klingberg et al., 1987; Saari et al., 1990; Dubovicky et al., 1997) and even no change in motor activity (Klingberg et al., 1987; Ishikawa et al., 1997; Sanchis-Segura and Aragon, 2002) have been described following MSG treatment. It has also been shown that spontaneous activity does not differ in MSG-treated rats from controls, but apomorphine- or ethanol-challenged motor activity decreases after MSG-treatment (Ali et al., 2000; Sanchis-Segura and Aragon, 2002). As pointed out by several other investigators, the diver-sity in changes in locomotor activity following MSG treatment may depend on the treatment paradigm, the different apparatus employed, the age of the ani-mals and the length and time of observation (Iwata et al., 1979; Miyabo et al., 1985; Klingberg et al., 1987; Hlinak et al., 2005). We found that the early postnatal hyperactivity of MSG-treated rats ceases after 3 weeks of age, and a slight hypoactivity can be observed at 8 weeks of age. Taking into account that MSG-treated rats were significantly smaller than their control littermates (see bodyweight of the animals), the observed initial hyperactivity is even more considerable. Our observations are consistent with some previous findings that have described hyperactivity at 2-3 weeks of age followed by no essential or slight differences between control and MSG-treated pups at older ages (Squibb et al., 1981; Klingberg et al., 1987). The observed hypo-activity at 8 weeks of age was a subtle difference compared to the control group, only represented by the covered area, while other parameters showed no significant difference. This is in accordance with the observations of Ali et al. (2000), who found no significant differences in locomotor activity at 2 months of age. Although our data do not solve the problem of discrepancy between the reported loco-motor alterations caused by neonatal MSG treat-ment, our results show that MSG treatment causes temporary increases in locomotor behavior, which is more pronounced during the first few postnatal weeks, followed by a subtle hypoactivity which may be prolonged during adulthood as observed by oth-ers (Hlinak et al., 2005). Our earlier observations on the neurobehavioral development of MSG-treated rats have also showed that MSG treatment does not

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cause permanent alterations, but only delays the appearance of some reflexes and leads to temporary changes in reflex performance and motor coordina-tion signs (Kiss et al., 2005). The major finding of our present study is the markedly altered novelty-seeking behavior in MSG-treated rats. MSG-treated pups showed an altered behavioral pattern in all tested signs in the nov-elty exploration test. Control animals were clearly interested in the novel object introduced in the last trial: they spent more time with ambulation with a decreased habituation, covered a larger area, spent less time with grooming and spent more time in the proximity of the novel object. The observed behav-ior of control rats is in accordance with the expected behavior of rats subjected to a novel environment (Heyser et al., 2004; Hlinak et al., 2005). In contrast to control rats, MSG-treated pups were less active, spent more time with grooming and spent signifi-cantly less time near the novel object during trial 4. Perinatal administration of numerous drugs and toxic agents has been shown to influence novelty-seeking behavior in rats (Ledig et al., 1998; Adriani et al., 2003; Heyser et al., 2004). However, little is known about the influence of neonatal MSG treat-ment on the novelty exploration. Previous reports (Dunn and Webster, 1985) have documented no alteration in grooming behavior when MSG-treated rats were subjected to an open-field (novelty). In accordance, in the first part of our experiments we did not find differences in the grooming behavior between control and MSG-treated rats. However, when novel objects were placed in the open field (second part of the experiment), significant differ-ences in the grooming behaviors were observed. In an open-field paradigm with successive trials in the same environment, a decrease of habituation has been found in adult rats neonatally treated with MSG (Dubovicky et al., 1997; Hlinak et al., 2005). These reports are in accordance with our results showing that habituation decreases in MSG-treated rats when subjected to the same environment (tri-als 2 and 3). Furthermore, our results show a clear difference between the novelty-seeking behavior of MSG-treated and control rats when subjected to a novel object in the open-field. Although the exact mechanism of the effects of MSG on novelty seeking cannot be clarified based on our present results, it seems probable that morphological

and/or biochemical changes induced in the brain by MSG treatment are responsible for the altered behav-ior. It is known that neonatal MSG treatment results in neurochemical changes, endocrinological altera-tions and damage of several brain structures. One of the most apparent changes is the extensive neuronal death in the arcuate nucleus, which can also be used to verify the effectiveness of the MSG treatment (Miquel et al., 2003; Kiss et al., 2005). Furthermore, it has been described that neonatal MSG treatment causes destruction and morphological changes of the CA1 hippocampal structure (Kubo et al., 1993; Ishikawa et al., 1997; Beas-Zarate et al., 2002), reduction of the volume of the subfornical organ (Pesini et al., 2004) and neuronal loss in the cerebral cortex (Gonzalez-Burgos et al., 2001; Chaparro-Huerta et al., 2002). Locomotor activity is known to increase when animals are subjected to a novel environment and this behavior is closely related to the hippocampus (Hlinak et al., 2005). The mark-edly changed behavior of MSG-treated rats in the novel environment may be related to the structural and neurochemical changes in the hippocampus. Also, the close relationship of the mesolimbic dopa-minergic system with novelty-seeking behavior and with the arcuate nucleus is well-established (Miquel et al., 2003; Bardo and Dwoskin, 2004; Schmidt and Beninger, 2006). Neonatal MSG treatment interferes with the dopaminergic system at various brain levels (Dawson, 1986; Wallace and Dawson, 1990; Zelena et al., 1998; Lin and Pan, 1999; Nakagawa et al., 2000; Bodnar et al., 2001). It can be assumed that the destruction of the arcuate nucleus and other changes in the dopaminergic pathways upon MSG admin-istration may also be responsible for the observed behavioral changes. In summary, our present study shows that neonatal MSG treatment leads to early temporary changes in the locomotor activity followed by hypoactivity at 2 months of age. Furthermore, MSG-treated rats show a disturbed novelty-seeking behavior repre-sented by decreased activity when subjected to a novel object.

Acknowledgements

This work was supported by the Hungarian Science Research Fund (OTKA T046589, F 67830 and F 48908) and ETT439/2006.

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References

Adriani W, DD Seta, F Dessi-Fulgheri, F Farabollini and G Laviola (2003) Altered profiles of spontaneous novelty seek-ing, impulsive behaviorm and response to D-amphetamine in rats perinatally exposed to bisphenol A. Environ. Health Perspect. 111, 395-401.

Ali MM, M Bawari, UK Misra and GN Babu (2000) Locomotor and learning deficits in adult rats exposed to monosodium-L-glutamate during early life. Neurosci. Lett. 284, 57-60.

Araujo PE and J Mayer (1973) Activity increase associated with obesity induced by monosodium glutamate in mice. Am. J. Physiol. 225, 764-765.

Archer T, T Palomo and A Fredriksson (2002) Neonatal 6-hydroxydopamine-induced hypo/hyperactivity: blockade by dopamine reuptake inhibitors and effect of acute D-amphet-amine. Neurotox. Res. 4, 247-266.

Archer T, N Schroder and A Fredriksson (2003) Neurobehav-ioural deficits following postnatal iron overload: II Instrumental learning performance. Neurotox. Res. 5, 77-94.

Babai N, T Atlasz, A Tamas, D Reglodi, P Kiss and R Gabriel (2005) Degree of damage compensation by various PACAP treatments in monosodium glutamate-induced retina degen-eration. Neurotox. Res. 8, 227-233.

Babai N, T Atlasz, A Tamas, D Reglodi, G Toth, P Kiss and R Gabriel (2006) Search for the optimal monosodium gluta-mate treatment schedule to study the neuroprotective effects of PACAP in the retina. Ann. NY Acad. Sci. 1070, 149-155.

Bardo MT and LP Dwoskin (2004) Biological connection between novelty- and drug-seeking motivational systems. Nebr. Symp. Motiv. 50, 127-158.

Beas-Zarate C, MI Perez-Vega and I Gonzalez-Burgos (2002) Neonatal exposure to monosodium L-glutamate induces loss of neurons and cytoarchitectural alterations in hippocampal CA1 pyramidal neurons of adult rats. Brain Res. 952, 275-281.

Beninger RJ, A Jhamandas, H Aujla, L Xue, RV Dagnone, RJ Boegman and K Jhamandas (2002) Neonatal exposure to the glutamate receptor antagonist MK-801: effects on locomo-tor activity and pre-pulse inhibition before and after sexual maturity in rats. Neurotox. Res. 4, 477-488.

Bodnar I, P Gooz, H Okamura, BE Toth, M Vecsernye, B Halasz and GM Nagy (2001) Effect of neonatal treatment with monosodium glutamate on dopaminergic and L-DOPA-ergic neurons of the medial basal hypothalamus and on prolactin and MSH secretion of rats. Brain Res. Bull. 55, 767-774.

Chaparro-Huerta V, MC Rivera-Cervantes, BM Torres-Mendoza and C Beas-Zarate (2002) Neuronal death and tumor necrosis factor- response to glutamate-induced exci-totoxicity in the cerebral cortex of neonatal rats. Neurosci. Lett. 333, 95-98.

Dawson R (1986) Developmental and sex-specific effects of low dose neonatal monosodium glutamate administration on mediobasal hypothalamic chemistry. Neuroendocrinology 42, 158-166.

Dawson R and JF Lorden (1981) Behavioral and neurochemi-cal effects of neonatal administration of monosodium L-glu-

tamate in mice. J. Comp. Physiol. Psychol. 95, 71-84.Dubovicky M, D Tokarev, I Skultetyova and D Jezova (1997)

Changes in exploratory behavior and its habituation in rats neonatally treated with monosodium glutamate. Pharmacol. Biochem. Behav. 56, 565-569.

Dunn AJ and EL Webster (1985) Neonatal treatment with monosodium glutamate does not alter grooming behavior induced by novelty or adrenocorticotropic hormone. Behav. Neur. Biol. 44, 80-89.

Fisher KN, RA Turner, G Pineault, J Kleim and MJ Saari (1991) The postweaning housing environment determines expression of learning deficit associated with neonatal monosodium glutamate (M.S.G.). Neurotoxicol. Teratol. 13, 507-513.

Frieder B and VE Grimm (1987) Prenatal monosodium gluta-mate causes long-lasting cholinergic and adrenergic changes in various brain regions. J. Neurochem. 48, 1359-1365.

Gonzalez-Burgos I, MI Perez-Vega and C Beas-Zarate (2001) Neonatal exposure to monosodium glutamate induces cell death and dendritic hypotrophy in rat prefrontocortical pyra-midal neurons. Neurosci. Lett. 297, 69-72.

Harry CJ (1998) Developmental neurotoxicology, In: Reproductive and Developmental Toxicology (Korach KS, Ed.) (Marcel Dekker, Inc.), pp 211-257.

Heyser CJ, M Pellitier and JS Ferris (2004) The effects of methylphenidate on novel object exploration in weanling and periadolescent rats. Ann. NY Acad. Sci. 1021, 465-469.

Hlinak Z, D Gandalovicova and I Krejci (2005) Behavioral deficits in adult rats treated neonatally with glutamate. Neurotoxicol. Teratol. 27, 465-473.

Ishikawa K, T Kubo, S Shibanoki, A Matsumoto, H Hata and S Atai (1997) Hippocampal degeneration inducing impair-ment of learning in rats: model of dementia? Behav. Brain Res. 83, 39-44.

Iwata S, M Ichimura, Y Matsusawa, Y Takasaki and M Sasaoka (1979) Behavioral studies in rats treated with monosodium L-glutamate during the early stages of life. Toxicol. Lett. 4, 345-357.

Kabbaj M, DP Devine, VR Savage and H Akil (2000) Neurobiological correlates of individual differences in nov-elty-seeking behavior in the rat: differential expression of stress-related molecules. J. Neurosci. 20, 6983-6988.

Katz RJ (1983) Neonatal monosodium glutamate differentially alters two models of behavioral activity in conjunction with reduced hypothalamic endorphins. Physiol. Behav. 31, 147-151.

Kim YW, DW Choi, YH Park, JY Huh, KC Won, KH Choi, SY Park, JY Kim and SK Lee (2005) Leptin-like effects of MTII are augmented in MSG-obese rats. Regul. Pept. 127, 63-70.

Kiss P, A Tamas, A Lubics, M Szalai, L Szalontay, I Lengvari and D Reglodi (2005) Development of neurological reflexes and motor coordination in rats neonatally treated with mono-sodium glutamate. Neurotox. Res. 8, 235-244.

Kiss P, A Tamas, A Lubics, I Lengvari, M Szalai, D Hauser, ZS Horvath, B Racz, R Gabriel, N Babai, G Toth and D Reglodi (2006) Effects of systemic PACAP treatment in monoso-dium glutamate-induced behavioral changes and retinal degeneration. Ann. NY Acad. Sci. 1070, 365-370.

Klingberg H, J Brankack and F Klingberg (1987) Long-term

NEONATAL MSG & ALTERED BEHAVIORS IN RATS 93

effects on behavior after postnatal treatment with monoso-dium-L-glutamate. Biomed. Biochim. Acta 46, 705-711.

Koehl M, V Lemaire, M Vallee, N Abrous, PV Piazza, W Mayo, S Maccari and M Le Moal (2001) Long term neuro-developmental and behavioral effects of perinatal life events in rats. Neurotox. Res. 3, 65-83.

Kostrzewa RM (1999) Selective neurotoxins, chemical tools to probe the mind: the first thirty years and beyond. Neurotox. Res. 1, 3-25.

Kostrzewa RM, JP Kostrzewa and R Brus (2003) Dopamine receptor supersensitivity: an outcome and index of neurotox-icity. Neurotox. Res. 5, 111-118.

Kubo T, R Kohira, T Okano and K Ishikawa (1993) Neonatal glutamate can destroy the hippocampal CA1 structure and impair discrimination learning in rats. Brain Res. 616, 311-314.

Ledig M, R Misslin, E Vogel, A Holownia, JC Copin and G Tholey (1998) Paternal alcohol exposure: develop-mental and behavioral effects on the offspring of rats. Neuropharmacology 37, 57-66.

Lin JY and JT Pan (1999) Single-unit activity of dorsomedial arcuate neurons and diurnal changes of tuberoinfundibular dopaminergic neuron activity in female rats with neonatal monosodium glutamate treatment. Brain Res. Bull. 48, 103-108.

Lubics A, D Reglodi, A Tamas, P Kiss, M Szalai, L Szalontay and I Lengvari (2005) Neurological reflexes and early motor behavior in rats subjected to neonatal hypoxic-ischemic injury. Behav. Brain Res. 157, 157-165.

Miquel M, L Font, C Sanchis-Segura and CM Aragon (2003) Neonatal administration of monosodium glutamate prevents the development of ethanol- but not psychostimulant-induced sensitization: a putative role of the arcuate nucleus. Eur. J. Neurosci. 17, 2163-2170.

Mistlberger RE and MC Antle (1999) Neonatal monosodium glutamate alters circadian organization of feeding, food anticipatory activity and photic masking in the rat. Brain Res. 842, 73-83.

Miyabo S, I Yamamura, E Ooya, N Aoyagi, Y Horikawa and S Hayashi (1985) Effects of neonatal treatment with mono-sodium glutamate on circadian locomotor rhythm in the rat. Brain Res. 339, 201-208.

Nakagawa T, K Ukai, T Ohyama, Y Gomita and H Okamura (2000) Effects of chronic administration of sibutramine on body weight, food intake and motor activity in neonatally monosodium glutamate-treated obese female rats: relation-ship of antiobesity effect with monoamines. Exp. Anim. 49, 239-249.

Palomo T, RJ Beninger, RM Kostrzewa and T Archer (2003) Brain sites of movement disorder: genetic and environmen-tal agents in neurodevelopmental perturbations. Neurotox. Res. 5, 1-26.

Pesini P, JL Rois, L Menendez and S Vidal (2004) The neo-natal treatment of rats with monosodium glutamate induces morphological changes in the subfornical organ. Acta Histol. Embryol. 33, 273-277.

Pizzi WJ and JE Barnhart (1976) Effects of monosodium glu-tamate on somatic development, obesity and activity in the mouse. Pharmacol. Biochem. Behav. 5, 551-557.

Poon TK and DP Cameron (1978) Measurement of oxygen consumption and locomotor activity in monosodium gluta-mate-induced obesity. Am. J. Physiol. 234, E532-E534.

Reddy GR, A Suresh, KS Murthy and CS Chetty (2002) Lead neurotoxicity: heme oxigenase and nitric oxide synthase activities in developing rat brain. Neurotox. Res. 4, 33-39.

Reglodi D, P Kiss, A Tamas and I Lengvari (2003). The effects of PACAP and PACAP antagonist on the neurobehavioral development of newborn rats. Behav. Brain Res. 140, 131-139.

Saari MJ, S Fong, A Shivji and JN Armstrong (1990) Enriched housing masks deficits in place navigation induced by neonatal monosodium glutamate. Neurotoxicol. Teratol. 12, 29-32.

Sanchis-Segura C and CM Aragon (2002) Consequences of monosodium glutamate or goldthioglucose arcuate nucle-us lesions on ethanol-induced locomotion. Drug Alcohol Depend. 68, 189-194.

Schmidt WJ and RJ Beninger (2006) Behavioral sensitization in addiction, schizophrenia, Parkinson`s disease and dyski-nesia. Neurotox. Res. 10, 161-166.

Segura-Aguilar J and RM Kostrzewa (2004) Neurotoxins and neurotoxic species implicated in neurodegeneration. Neurotox. Res. 6, 615-630.

Segura-Aguilar J and RM Kostrzewa (2006) Neurotoxins and neurotoxicity mechanisms. An overview. Neurotox. Res. 10, 263-285.

Seress L (1982) Divergent effects of acute and chronic mono-sodium glutamate treatment on the anterior and posterior parts of the arcuate nucleus. Neuroscience 7, 2207-2216.

Squibb RE, HA Tilson, OA Meyer and CA Lamartiniere (1981) Neonatal exposure to monosodium glutamate alters the neurobehavioral performance of adult rats. Neurotoxicology 2, 471-484.

Stansfield KH, RM Philpot and CL Kirstein (2004) The animal model of sensation seeking: the adolescent rat. Ann. NY Acad. Sci. 1021, 453-458.

Tamas A, R Gabriel, B Racz, V Denes, P Kiss, A Lubics, I Lengvari and D Reglodi (2004) Effects of pituitary adenyl-ate cyclase activating polypeptide in retinal degeneration induced by monosodium-glutamate. Neurosci. Lett. 372, 110-113.

Urena-Guerrero ME, SJ Lopez-Perez and C Beas-Zarate (2003) Neonatal monosodium glutamate treatment modifies glutamic acid decarboxylase activity during rat brain postna-tal development. Neurochem. Int. 42, 269-276.

Wallace DR and R Dawson Jr (1990) Effect of age and mono-sodium-L-glutamate (MSG) treatment on neurotransmit-ter content in brain regions from male Fischer-344 rats. Neurochem. Res. 15, 889-898.

Zelena D, D Jezova, Z Acs and GB Makara (1998) Monosodium glutamate lesions inhibit the N-methyl-D-aspartate-induced growth hormone but not prolactin release in rats. Life Sci. 62, 2065-2072.

Zheng XG, BP Tan, XJ Luo, W Xu, XY Yang and N Sui (2004) Novelty-seeking behavior and stress-induced locomotion in rats of juvenile period differentially related to morphine place conditioning in their adulthood. Behav. Processes 65, 15-23.