activity such as d-amphetamine induced loco- ... the nucleus accumbens reduce spontaneous loco- ... ever, the increase in DA metabolism was more pro-.
Neuroscience Vol. 66, No. 2, pp. 467473, 1995
~ Pergamon
0306-4522(94)00605 -9
Elsevier ScienceLtd Copyright © 1995 IBRO Printed in Great Britain. All rights reserved 0306-4522/95 $9.50 + 0.00
PRENATAL CORTICOSTERONE INCREASES SPONTANEOUS A N D d-AMPHETAMINE INDUCED LOCOMOTOR ACTIVITY AND BRAIN DOPAMINE METABOLISM IN PREPUBERTAL MALE AND FEMALE RATS R. D I A Z , * t S. O. O G R E N , * M. B L U M ~ and K. F U X E * *Department of Neuroscience, Division of Cellular and Molecular Neurochemistry, Karolinska lnstitutet. 171 77 Stockholm, Sweden ++Dr A. M. Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York. NY, U.S.A. Akstraet--Recently, both glucocorticoid receptor immunoreactivity and glucocorticoid receptor messenger RNA levels were found in multiple brain areas, especially in the neuroepithelium during the late prenatal development of the rat brain. To better understand the potential influence of stress on fetal brain development by release of maternal adrenocortical steroids, we have investigated the effects of corticosterone administration to pregnant rats on the locomotor activity of their prepubertal offspring. On day 16 of pregnancy female rats were implanted with either placebo or corticosterone pellets (release of 2.4 mg/day for seven days). After birth their offspring were nursed by foster mothers to avoid any postnatal effects of the corticosterone pellets. At three weeks of age, the offspring were tested for spontaneous motor behaviours. Both male and female offspring from corticosterone treated mothers showed significantly increased spontaneous ambulation, motility and rearing compared to placebo treated groups. No significant sex differences were found in locomotor activity between male and female offspring from placebo groups. Following d-amphetamine (1.5 mg/kg) treatment, a preferential dopamine releasing agent, we observed a significant increase in ambulation, motility and rearing activity in the male offspring treated with corticosterone. In the female offspring, only the rearing activity was significantly higher after d-amphetamine treatment in the prenatal corticosterone group compared with the placebo treated group. Basal dopamine metabolism (dihydroxyphenylacetic acid/dopamine ratio) was increased in the dorsal striatum and ventral striatum of male and female offspring from corticosterone-treated dams. In the male offspring, corticosterone treatment was associated with a disappearance of the right side dominance of dopamine metabolism in the dorsal striatum. These results suggest that prenatal administration of corticosterone in low physiological doses can affect the postnatal development of spontaneous locomotor activity and dopamine function in a manner which is partly different in the two sexes. The effects observed may be mediated by direct activation of corticosterone receptors in the fetal brain.
M a n y of the nigrostriatal and mesolimbic dopaminergic (DA) pathways of the adult rat express glucocorticoid receptors and may directly respond to circulating adrenal steroids) TM For example, various DA-mediated behaviours such as wheel-running and locomotion in the open-field are decreased by adrenalectomy and increased by corticosterone treatment. 4'29 In addition, changes in corticosterone levels affect dopamine release and turnover, 2'8'~9'27'32 dopamine receptor density and affinity ~'~°'3°and neuropeptide gene expression (for a review, see Ref. 22) in both striatal and accumbens neurons. However, little is known about the effects of adrenal steroids on the early development of these dopaminergic pathways. tTo whom correspondence should be addressed. Abbreviations: DA, dopamine; DOPAC, dihydroxypheny-
lacetic acid; EDTA, ethylenediamine tetraacetic acid; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PFC, prefrontal cortex; 6-OHDA, 6-hydroxydopamine. 467
Most of our information comes from studies on prenatal stress which suggest that rats exposed to stress during the last trimester of pregnancy produce offspring which show alterations in locomotor or exploratory activity (for review, see Ref. 31). Prenatal stress also appears to modify the levels of the monoamines in various brain regions, 12"13'14'23 suggesting a link between plasticity in the central monoaminergic systems and the observed functional changes. Prenatal stress has been shown to elevate plasma corticosterone in the damfl 4'31 This steroid can also readily cross the placenta barrier 34 and is also produced during late fetal brain development by the active fetal zone of the adrenal cortex. 33 Recently, it was reported 7 that during fetal brain development both glucocorticoid receptor (GR) immunoreactivity and m R N A levels are present in multiple brain areas, including regions containing the monoaminergic system. Thus, the presence of G R in the fetal brain suggests a possible role of glucocorticoids in normal
R. Diaz et al.
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b r a i n d e v e l o p m e n t a n d m a y help to explain some o f the changes observed after m a t e r n a l stress. The aim o f the present study was to determine the possible influence o f m a t e r n a l corticosterone o n the nigrostriatal a n d mesolimbic D A pathways. A low dose of corticosterone was administered c o n t i n u o u s l y via a pellet i m p l a n t e d in the p r e g n a n t d a m d u r i n g the last trimester of gestation. T h e l o c o m o t o r activity a n d d o p a m i n e m e t a b o l i s m in the right a n d left frontal lobe, the dorsal (striatum) a n d ventral striatum (nucleus a c c u m b e n s a n d olfactory tubercle) were evaluated in the p r e p u b e r t a l male a n d female offspring.
EXPERIMENTAL PROCEDURES
Twenty-four nulliparus pregnant Sprague-Dawley rats (300 g body weight) with a defined day of fertilization were purchased from ALAB (Stockholm, Sweden). Birth normally occurs on day 22 of gestation. On the arrival day (day 12 of pregnancy), females were housed singly and randomly assigned to placebo or corticosterone groups. All rats were kept in a temperature and humidity controlled room under a regular day and night cycle (lights on at 06.00 h and off at 18.00 h) with free access to food pellets and water bottles. On day 16 of pregnancy, animals received s.c. implantation, under light halothane anaesthesia, of either a corticosterone pellet (Innovative Research of America, Toledo, Ohio; 50 mg pellet; 21 day-release) with a constant release rate of 2.40 mg/day for seven days, or a placebo for corticosterone pellets. According to the manufacturer a 50 mg corticosterone pellet will result in ~ 4 #g/100ml of plasma levels (values comparable to basal resting conditions) in a rat weighing 200-300 g. These levels may be slightly lower in a pregnant rat with a larger extracellular volume. Within 6 h after birth (day = 1 of age), all litters were reduced to eight pups with as equal numbers of males and females as possible and nursed by a foster mother to avoid any postnatal effects of exogenous eorticosterone. The offspring were weaned at 21 days of age, 1 h before the light went-off, and maintained in groups of five to six separated by sex and treatment. They were weighed on day 1 and at 21 days of age. Behavioural testing At the age of three weeks, ambulation, motility and rearing were evaluated in 12 offspring (two animals/group) simultaneously by means of a multicage, red and infraredsensitive motion detection system} 2a The system is fully computerized and uses beams of infrared and red lights in combination with vertical and horizontal photocell arrays to detect movements of animals. The experimental setup (Motron activity apparatus) used in this study included two horizontal and one vertical array of photocell detectors per cage. Rearing was measured by counting the number of times an animal stands on its hindlegs so that its head breaks any of the six invisible infrared beams passing horizontally through the cage at a height of 9 cm above the cage floor. Motility was measured by counting all movements of a distance of 4 cm detected by horizontal photocells, and represents a measurement of general activity. Ambulation was measured by counting the number of times an animal has moved from one box containing horizontal photocell detectors to the other side (a distance of at least 32 cm). Testing took place during the early part of the light cycle between 09.00-14.00 h. All animals tested were brought to a room adjacent to the behavioural one, 2 hours prior to the beginning of the testing, weighed and marked on the tail.
The animals were kept in groups of six separated by sex and treatment and food was available in their cages. Only two rats of each sex were used for any given treatment to minimize litter effects. The animals were then placed in the activity boxes and locomotor activity was recorded for 60 min (habituation phase). Thereupon, animals were injected with d-amphetamine (1.5 mg/kg, i.p.) and the locomotor activity was recorded for an additional 60-min period. Since d-amphetamine-induced locomotion develops within 20 min, the results for d-amphetamine were analysed during the 20-50-min interval (e.g., a 30-min period) after drug injection during which the peak effect is seen. Measurement of dopamine and dihydroxyphenylacetic acid One week after the behavioural testing was performed, four to six female and male offspring of each group were taken from the animal house and kept in an adjacent room, at least for 2 h before decapitation. After decapitation, the brains were rapidly removed and chilled in 0.9% saline on ice for one minute. The right and left frontal lobes (mainly frontal and cingulate cortex) were removed by orienting the brain with the ventral surface upwards, making a cut rostral to the olfactory tubercle and removing the olfactory bulb and cortex. The brain was then oriented dorsally and split in the midline. The midline tissue, mainly the septum was gently removed. The right and left dorsal striatum were carefully removed from the surrounding external capsule. The brain was then oriented again with the ventral surface upwards and the diencephalon was removed by making a cut in front of the optic chiasm. The right and left olfactory tubercle and accumbens nuclei (ventral striatum) were then removed, using the lateral olfactory tract as a landmark. All tissues were dissected on a cold plate. Immediately after removal all tissues were frozen on dry ice and individually stored at - 7 0 ° C in microfuge tubes until the day of biochemical analysis. At the time of the analysis the tissues were weighed and sonicated in 0. I M perchloric acid (5 vol) and centrifuged at 10,000g for 10 min. The supernatants were then injected into a reversed phase column (supercosil LC-18, 7.5 × 4.6 mm i.d., 3/~m average particle in diameter; Supelco, Bellafonte, USA). Electrochemical detection was performed by means of a glassy carbon working electrode (LC-4A, Bioanalytical systems, U.S.A.) set at + 0.7 V. The mobile phase consisted of a 0.05 M sodium phosphate, 0.03 M citrate acid buffer, 0.1 mM EDTA and various amounts of methanol and sodium-l-octane sulphonic acid. The retention time and heights of the peaks of the endogenous compounds were compared with external standards containing DA and dihydroxyphenylacetic acid (DOPAC) within the same range as the specimens and the data were expressed as ng/g of tissue wet weight. Stat&tics A one-way ANOVA was used to analyse the behavioural data. When differences were found between groups, post hoc individual comparisons were carried out with Student's t-test. Dopamine metabolism (DOPAC/DA), DA and DOPAC levels were analyzed by the nonparametric Mann-Whitney U-test followed by Bonferroni's correction. A difference of P < 0.05 was considered to be statistically significant. RESULTS
Prenatal corticosterone did n o t significantly alter the length of gestation or affect the body weight (g) o f the offspring, m e a s u r e d at birth (females: 5.7 ___0.08 vs 6.0 + 0.07; males: 6.2 + 11 vs 6.5 _+ 0.12) a n d three weeks o f age (females: 37.8 + 0.77 vs 37.8 + 1.55; males: 39.8 _+ 0.53 vs 37.4 +_ 1.88).
Prenatal corticosterone, DA and locomotor behaviour
Locomotor behaviour Spontaneous locomotor behaviour was examined for a period of 60 rain. The accumulated locomotor counts are shown in Table 1. N o significant sex differences were found in the placebo groups with regard to ambulation, motility and rearing activity in rats aged three weeks. Rats of both sexes subjected to prenatal corticosterone displayed significantly increased spontaneous ambulation, motility and rearing. Analysis of the exploration to the novel environment (activity measured during the first 15 rain) showed that all aspects of exploration (spontaneous ambulation, motility and rearing) appeared to be increased in the offspring of both sexes after corticosterone treatment (data not shown). At the end of the habituation period, just prior to d-amphetamine (1.5 mg/kg) treatment, the rats were inactive and most of them were sleeping. Following injection of d-amphetamine there was a significant increase in ambulation, motility and rearing in rats of both sexes (Table 1). This response was enhanced in male offspring that had received corticosterone prenatally, and in the case of rearing also in the female offspring that had received corticosterone prenatally (Table 1).
Biochemical analysis Regional dopamine levels. The prenatally corticosterone-treated male offspring showed a significant decrease in dopamine levels in both the right and left dorsal striatum as shown in Table 2. N o significant changes were observed in the frontal lobe and the ventral striatum (olfactory tubercle and nucleus ac-
cumbens) after corticosterone treatment as evaluated in the male offspring. In the female offspring the only significant change induced by the cortieosterone treatment was found in the ventral striatum on the left side where a significant reduction of D A levels had taken place. N o other changes were found neither in the frontal lobe nor in the dorsal striatum (Table 2). Regional dihydroxyphenylacetic acid levels. Significant changes induced by corticosterone treatment as evaluated in the male offspring were only observed in the dorsal striatum as shown in Table 2. In the dorsal striatum on the left side the corticosterone treatment had resulted in significant increases of D O P A C levels, while on the right side a significant reduction had taken place. No changes in D O P A C levels were observed within the frontal lobe and the ventral striatum. Regional dopamine metabolism. Changes in D A metabolism were evaluated by calculation of the ratio D O P A C to D A in the brain areas examined. As seen in Table 3, the corticosterone treatment resulted in increases of D A metabolism in the male offspring on the left side of the dorsal striatum and on both sides of the ventral striatum. The increases in D A metabolism were stronger in the dorsal striatum. The changes induced on the left side of the dorsal striatum in the male rats subjected to corticosterone treatment led to an absence of asymmetry in contrast to the case in the placebo group (Table 3). In the female offspring the corticosterone treatment led to the development of significant increases in D A metabolism on the left side of both dorsal and ventral striatum. In the frontal lobe and dorsal
Table 1. Effects of corticosterone administration to pregnant rats during the last trimester of gestation on locomotor behaviour of their prepubertal male and female offspring (21-22 days old) Treatment Spontaneous Males Placebo Corticosterone Females Placebo Corticosterone d-Amphetamine Males Placebo Corticosterone Females Placebo Corticosterone
469
Ambulation
Motility
Rearing
37 + 5 64 + 9*
1330 + 141 2084 + 217'
102 + 22 199 _ 33*
33 + 3 45 _ 5*
1208 + 116 1746 + 168"
58 + 7 118 + 14"
57 + 10 111 + 13*
2094 + 214 3085 + 278*
80 + 27 176 + 43*
55 + 9 92 __. 18
2051 ___294 2673 + 358
72 + 22 253 + 64
The spontaneous locomotor activity shows the accumulated counts (60-min testing period). The results are represented as means ___S.E.M. (n = 14-17). At the end of the 60-min period (habituation period), the rats were injected with d-amphetamine (1.5 mg/kg) and their locomotor activity was recorded for an additional 60 min. The results for d-amphetamine are shown as means + S.E.M. during the 20~50 min interval after drug injection at the peak effect of the compound. *P < 0.05 compared with respective placebo treated group.
470
R. Diaz et al. Table 2. Effects of corticosterone administration to pregnant rats during the last trimester of gestation on the levels of dopamine and dihydroxyphenylacetic acid in specific brain areas of their offspring (30 days of age) Frontal Cortex
Treatment Males Placebo(L) Cortico(L) Placebo(R) Cortico(R) Females Placebo(L) Cortico(L) Placebo(R) Cortico(R)
Dorsal Striatum
Ventral Striatum
DA (ng/g)
DOPAC (ng/g)
DA (ng/g)
DOPAC (ng/g)
DA (ng/g)
DOPAC (ng/g)
50 ___12 (5) 6 5 + 13 (6) 47 + 5 (4) 49+7 (5)
25 + 7 (5) 20+2 (6) 19 + 3 (4) 19+1 (5)
5850 ___419 (4) 3370+214"* (5) 3904 + 134 (5) 2988+279* (5)
1565 + 110 (4) 2346+174" (5) 2645 + 188 (5) 1914+156" (5)
2768 + 79 738 + 36 (4) (4) 2323+233 957+175 (5) (5) 2152 + 466 635 + 136 (5) (5) 2118+199 9 0 2 + 4 9 (5) (5)
63 + 9 (4) 118+26 (5) 94 __+14 (5) 71 + 17 (5)
30 + 5 (4) 56+11 (5) 50 + 10 (5) 61+13 (5)
3979 + 939 (5) 3021 +653 (5) 4454 + 361 (5) 3269+221 (6)
1323 + 330 (5) 1445+278 (5) 1357 + 114 (5) 1500+176 (6)
2192 + 236 (5) 1435+127" (6) 1757 + 232 (5) 1737+138 (6)
691 __+183 (5) 638+37 (6) 652 __+127 (5) 700+ 112 (6)
Data represent the means + S.E.M. n is indicated in parenthesis; ng/g means n~,gof tissue wet weight. Statistical analysis was performed according to the non-parametric Mann-Whitney U-test with Bonferrone's correction. **P < 0.01; *P < 0.05 compared with the respective placebo from the same sex and side of brain. L = left; R = right; Cortico = corticosterone.
striatum, corticosterone t r e a t m e n t led to significant increases in D A m e t a b o l i s m o n the right side b u t that was n o t the case in the ventral striatum. DISCUSSION T h e m a i n new findings in this study are t h a t c o n t i n u o u s exposure to a relatively low level of corticosterone during the last trimester of gestation in rats increased s p o n t a n e o u s a n d d - a m p h e t a m i n e - i n duced l o c o m o t o r activity. These changes m a y be linked to the d e m o n s t r a t e d uni- a n d / o r bilateral increases o f D A m e t a b o l i s m in the dorsal a n d ventral striatum, areas of the brain k n o w n to be involved in the m e d i a t i o n o f m o t o r activity a n d e x p l o r a t i o n ) ~ M o s t of the actions of gluco- a n d mineralocorti-
coids are mediated t h r o u g h intracellular receptors, which m a y undergo translocation to the nucleus u p o n activation by the hormones. They regulate transcription o f specific genes, c o n t a i n i n g glucocorticoid responsive elements (for a review, see Ref. 16). Two classes o f corticosteroid receptors, Type I a n d Type II, have been described in the brain. Type I receptors, k n o w n as the mineralocorticoid receptors (MR), bind b o t h corticosterone a n d aldosterone with an equally high affinity (Kd ~ 0.5 nM), while Type II receptors ( G R ) preferentially bind corticosterone, b u t with a lower affinity (2.5-5.0 nM).Ul"2'28'29 Corticosterone readily crosses the placental barrier 34 a n d glucocorticoid receptor protein a n d m R N A in the neuroepithelium are expressed during fetal b r a i n d e v e l o p m e n t (for review, see Ref. 25). Moreover, we recently f o u n d
Table 3. Effects of corticosterone administration to pregnant rats during the last trimester of gestation on the dihydroxyphenylacetic acid/dopamine ratio in specific brain areas of their offspring (30 days old) Treatment Males Placebo(L) Cortico(L) Placebo(R) Cortico(R) Females Placebo(L) Cortico(L) Placebo(R) Cortico(R)
Frontal Cortex x 100
Dorsal Striatum x 100
Ventral Striatum x 100
49 + 3 35 + 5 40 ___3 41 + 5
27 _+ 1 70 + 5* 68 ___5 66 + 7
27 __+2 40 + 5* 29 + 1 44 + 3*
50 + 10 53 ___11 53 ___5 89 + 6*
33 + 5 50 _ 4* 31 ___3 45 + 3*
30 + 6 46 _+ 3* 37 +_4 40 + 5
Data represent the means _+ S.E.M. n = 445 animals/group. Statistical analysis was performed according to the non-parametric Mann Whitney U-test with Bonferroni's correction. *P < 0.05 compared with the respective placebo from the same sex and side of brain. L = left; R = right; Cortico = corticosterone.
Prenatal corticosterone, DA and locomotor behaviour that there is expression of M R m R N A during late fetal brain development (unpublished observations). Therefore it seems likely that changes in maternal adrenocorticoid levels can affect fetal brain development by activating G R and MR, depending on the concentration reached in the fetal brain. The free corticosterone levels in fetal brain depend upon various factors such as the activity of the 11-//-hydroxysteroid dehydrogenase, the normal placenta barrier to maternal adrenocorticoids and the concentration of corticosterone binding protein during pregnancy (for review, see Ref. 26). Since the plasma corticosterone levels obtained with 50 mg pellets is within the basal physiological range (about 2-4/~g/ml), it is reasonable to suggest that the observed effects of prenatal corticosterone treatment could be mediated primarily by activation of MRs. It is well known that the mesolimbic and nigrostriatal dopaminergic systems participate in regulating spontaneous motor activity and DA-induced motor activity such as d-amphetamine induced locomotion. ~1.2~Moreover, these neuronal systems express both G R and M R in the adult brain (for review, see Ref. 17). It is, therefore, possible that the observed effects of prenatal corticosterone on motor behaviour could have been mediated by direct actions upon the developing dopaminergic system, perhaps, by affecting maturation processes of these pathways, although indirect effects can also be of importance. Taken together, the observed results supports the view of important interactions between the adrenal steroids and the dopaminergic system. The behavioural effects observed in the corticosterone treated rats could reflect changes in different DA systems. Mesolimbic dopamine neurons, preferentially projecting to the nucleus accumbens, are important for both exploratory locomotion u and d-amphetamine-induced locomotion. 2~ However, a number of findings indicate that the DA mechanisms underlying the motor activity by DA stimulants like d-amphetamine differ from those underlying spontaneous or exploratory motor activity. 28 Moreover, there is evidence that structures outside the mesolimbic DA systems, e.g. the prefrontal cortex (PFC) may be involved in spontaneous locomotor activity. However, the role of PFC in d-amphetamine-induced locomotion is probably negligiblefl° Thus, 6-hydroxydopamine (6-OHDA) lesions of the PFC result in increased locomotor activity but fail to effect the locomotor responses to d-amphetamine. 5 On the other hand, 6-OHDA lesions of DA terminals within the nucleus accumbens reduce spontaneous locomotion and result in a blockade of d-amphetamineinduced hyperactivity. 2°'21 Stimulation of DA activity in the nucleus accumbens by direct injection of DA or d-amphetamine results into hyperactivity.9'z8 In view of the changes in DA metabolism, the increases in spontaneous locomotion observed after corticosterone treatment could be due to increased DA release or transmission in the nucleus accumbens.
471
The observed trend for decreases in DA metabolism in the PFC could possibly contribute to the hyperactivity seen in the male offspring, Since the female offspring did not display any decrease in DA metabolism in the PFC but an increase in the right lobe it may be hypothesized that male and female rats probably display differential changes in the pattern of locomotor behaviour which can be revealed under certain circumstances. This suggestion receives support from the finding that prenatal corticosterone increased the locomotor responses to d-amphetamine in a manner which was sex-dependent. It is notable that there exists unilateral or bilateral increases in DA metabolism in both prenatally corticosterone treated male and female rats. However, the increase in DA metabolism was more pronounced in the male than in the female offspring. The locomotor stimulatory effects of d-amphetamine at the dose used 1.5 mg/kg are probably largely mediated by dopamine release from terminals of mesolimbic dopaminergic neurons, projecting to the nucleus accumbens and olfactory tubercle. Amphetamine appears not to induce dopamine release in the neostriatum in male prepubertal ratsJ 5 This supports the view that also in the male prepubertal rat amphetamine-induced locomotion involves primarily the mesolimbic DA system. The lower locomotor response to d-amphetamine in the female offspring with the exception of the rearing response could therefore reflect a substantially lower DA release in relevant brain areas, e.g. the nucleus accumbens. Alternatively, since other DA containing areas of the brain such as the prefrontal cortex also appear to play a role in locomotor behaviour 2° the changes observed in the female may involve actions on both mesolimbic and mesocortical DA neurons. Another important finding is that the changes induced by corticosterone treatment were not symmetrical. Thus, we observed that in the male offspring corticosterone treatmenteliminated the DA asymmetry observed in the placebo group. This finding suggests that prenatal corticosterone exerts balancing effects on the maturation of DA neurons on the left and right side of the brain. However, in the female offspring corticosterone appeared to produce a dominance of DA metabolism on the right side in the case of the frontal lobe. These effects of prenatal corticosterone on DA metabolism could be mediated by a direct effect of prenatal corticosterone on neuronal maturation including DA neurons. Alternatively, these changes could be the result of compensatory mechanisms operating in these DA neurons in response to direct alterations by steroid hormones of the postsynaptic targets which could have affected e.g. the dopamine receptor levels and/or their coupling mechanisms (e.g., G proteins). In addition, it has been reported that glucocorticoids can regulate the gene expression of neurotrophic factors, which are known to play an important role during early brain development, including the development of DA neur-
472
R. Diaz et al.
ons. 3'6 Such actions of corticosterone could have markedly affected the pre- and postsynaptic features of the ascending D A neurons. CONCLUSIONS In summary, continuous exposure to low corticosterone via pellets to pregnant rats increase locomotor activity (both spontaneous and d-amphetamine-induced) which may be mainly linked to increases in ventral striatal dopamine metabolism in the prepubertal offspring. This treatment also results in a disappearance of dorsal striatal D A metabolism
asymmetry in the male offspring. These effects of corticosterone may be mediated by direct activation of M R s and possibly G R s in the fetal brain, controlling directly or indirectly the development and maturation of the ascending D A pathways, thus leading to long turn changes in the D A pathways to the dorsal and ventral striatum.
Acknowledgements--We would like to thank Ulla-Britt
Finnman and Susanne Andersson for technical assistance and Prof. Marta Weinstock for valuable comments on this manuscript. This work has been supported by a grant (014X-715) from the Swedish Research Council.
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