Dehydroepiandrosterone and monoamines in the limbic system of a genetic animal model of childhood depression
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European Neuropsychopharmacology (2008) 18, 255–261
w w w. e l s e v i e r. c o m / l o c a t e / e u r o n e u r o
Dehydroepiandrosterone and monoamines in the
limbic system of a genetic animal model of
childhood depression
O. Malkesman a,e , Y. Braw b,e , E. Ram c , R. Maayan c , A. Weizman c ,
N. Kinor d,e , G. Yadid d,e , A. Weller a,b,e,⁎
a
Interdisciplinary Program in the Brain Sciences, Bar-Ilan University, Israel
b
Department of Psychology, Bar-Ilan University, Israel
c
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center and Sackler, Faculty of Medicine,
Tel Aviv University, Beilinson Campus, Israel
d
Faculty of Life Sciences, Bar-Ilan University, Israel
e
Gonda (Goldschmied) Brain Research Center Bar-Ilan University, Israel
Received 29 January 2007; received in revised form 10 April 2007; accepted 27 June 2007
KEYWORDS Abstract
Childhood depression;
Monoamines; Monoamines and dehydroepiandrosterone (DHEA) levels were measured in a genetic animal model
DHEA; for childhood depression in four subcortical structures: nucleus accumbens (Nac), ventral tegmental
Limbic system; area (VTA), amygdala and hypothalamus. The “depressive-like” strain was the Flinders Sensitive
Animal model; Line (FSL), compared to their controls, Sprague–Dawley (SD) rats. Prepubertal FSL rats showed
FSL abnormal levels of only a few monoamines and their metabolites in these brain regions. This is in
contrast to former studies, in which adult FSL rats exhibited significantly higher levels of all the
monoamines and their metabolites measured. These different abnormal monoamine patterns
between the “depressed” prepubertal rats and their adults, may help to explain why depressed
children and adolescents fail to respond to antidepressant treatment as well as adults do. On the
other hand, FSL prepubertal rats exhibited the same pattern of abnormal DHEA basal levels as was
found in adults in previous experiments. The results from the current study may imply that
treatment with DHEA could be a promising novel therapeutic option for depressed children and
adolescents that fail to respond to common (monoaminergic) antidepressant treatments.
© 2007 Elsevier B.V. and ECNP. All rights reserved.
⁎ Corresponding author. Department of Psychology, Bar Ilan University, Ramat-Gan 52900, Israel. Tel.: +972 3 5318548; fax: +972 3 5350267.
E-mail address: weller@mail.biu.ac.il (A. Weller).
0924-977X/$ - see front matter © 2007 Elsevier B.V. and ECNP. All rights reserved.
doi:10.1016/j.euroneuro.2007.06.007256 O. Malkesman et al.
1. Introduction that can be explained by the interaction between the sigma 1
receptor agonist DHEAS (Maurice et al., 1996) and noradren-
In recent years, there has been increasing recognition of the aline, dopamine and serotonin (5-HT) neurotransmission (Dong
role played by particular subcortical structures [e.g. nucleus et al., 2007; Maayan et al., 2006). Enhancement of noradren-
accumbens (Nac), hypothalamus, ventral tegmental area aline (Delgado and Moreno, 2000), serotonin (Delgado, 2000;
(VTA) and amygdala] in the regulation of motivation, sleep, Dubrovsky, 2005) and dopamine (Yadid et al., 2000) neuro-
appetite, energy level, circadian rhythms, and responses to transmission is considered to have an antidepressant effect.
pleasurable and aversive stimuli — domains which are prom- In vitro experiments suggest that sigma ligands inhibit
inently affected in most depressed patients (Nestler et al., noradrenaline presynaptic re-uptake in brain synaptosomes
2002). These brain areas have been found to play critical (Kinouchi et al., 1989; Rogers and Lemaire, 1991) and increase
roles in depression (Koob et al., 1998; Wise, 1998). noradrenaline release (Kinouchi et al., 1989). The finding that
Many studies point to the Nac as the central region administration of DHEA increases hypothalamic serotonin
involved in, and mediating, activities relating to motivation levels (Abadie et al., 1993; Svec and Porter, 1997) supports
and hedonia (Phillips et al., 1991; Robinson and Berridge, the positive relationship between DHEA and brain serotonin
1993; Breiter et al., 1997). The Nac is a target of the and its possible effect in depression. It was also shown that
mesolimbic dopamine system, which arises in dopaminergic treatment with DHEA increased the dopamine content in the
neurons in the VTA of the midbrain. These VTA neurons also VTA and the Nac (Maayan et al., 2006) and that blockage of D1
innervate several other limbic structures, including the receptor or its downstream signaling molecules (AC and PKA)
amygdala and limbic regions of the neocortex (Nestler with specific antagonist could completely cancel the effect
et al., 2002). The amygdala is equally important for of DHEAS (Dong et al., 2007). These findings support the
conditioned responses to rewarding stimuli, including sub- positive relationship between DHEA/DHEAS and brain dopa-
stances of abuse and natural rewards (Everitt et al., 1999). mine and its possible effect in depression.
Another subcortical structure with a role in depression is the In addition, it has been proposed that DHEA and DHEAS
hypothalamus, which has long been known to mediate many may play a role in neurodevelopment, due to a transient
neuroendocrine and neuro-vegetative functions. Because of expression of steroidogenic enzyme P450 17-alpha hydroxy-
their unique importance and influence on depression, we lase (P450c17) (Compagnone et al., 1995) and the potential
focused on these four subcortical areas in the current ability of DHEA and DHEAS to aid in neuronal pathway
research: Nac, VTA, amygdala, and hypothalamus [another formation (Compagnone and Mellon, 1998).
important brain region which influences depression and Since DHEA may play an important role in depression, both
should be mentioned is the hippocampus; (for review see because of it's anti-depressive effect and it's role in neuronal
Dranovsky and Hen, 2006; Duman and Monteggia, 2006). pathway formation, we measured the levels of DHEA in the
Since the focus of the current study was on the limbic limbic system of “depressed-like” prepubertal rats and their
system, we did not examine this specific region]. controls, trying to find out whether the juveniles of this strain
Childhood depression has received attention as a signifi- show abnormal levels of DHEA as is found in depressed patients
cant clinical phenomenon only relatively recently. Major [Though peripheral DHEA and DHEAS might both have a role in
depression in children and adolescents is common, recurrent, depression (for review see Binello and Gordon, 2003) we focused
and associated with significant morbidity and mortality on DHEA levels in the limbic system because of it's positive
(Birmaher et al., 1996). Despite similarities in the clinical relationship with monoamines in these specific brain regions
picture and longitudinal course of major depression in (Abadie et al., 1993; Svec and Porter, 1997), while avoiding the
children, adolescents, and adults (Kovacs, 1996), there are influence of various endogenous factors that can influence the
notable differences in the neurobiological correlates and synthesis of DHEA(S) in the periphery, and are also impaired in
treatment response of depressed patients in these different depression and especially in childhood depression (Jensen and
age cohorts (Kaufman et al., 2001). Most notably, depressed Garfinkel, 1990; Dorn et al., 1997; Birmaher et al., 1996)].
prepubertal children fail to respond to antidepressant As mentioned above, serotonin, noradrenaline, and dopa-
treatment as well as adults do (Hazell et al., 1995; Keller mine are believed to be involved in mental depression
et al., 2001; Zalsman et al., 2006). For example tricyclic (Aghajanian, 1994; Elhwuegi, 2004). According to the mono-
antidepressants have not been shown to be more efficacious amine theory, depletion of serotonin and/or dopamine is one
than placebo for pediatric depression (Kye and Ryan, 1995; of the causes of depression (Piñeyro and Blier, 1999). Serotonin
Keller et al., 2001). This may indicate that some aspects of and dopamine depletion might contribute to depression by
pathophysiology in monoaminergic circuits are unique to affecting neurons in the limbic system (Nemeroff, 1998).
childhood depression (Axelson and Birmaher, 2001). In order Among the findings supporting a link between low synaptic
to identify unique circuits that might be implicated in serotonin and dopamine levels and depression is that
children suffering from depression and in attempt to examine cerebrospinal fluid (CSF) in depressed, and especially in
potential new antidepressant approaches for childhood suicidal patients contains reduced amounts of major serotonin
depression, we measured the basal levels of Dehydroepian- by-products (signifying reduced levels of serotonin in the brain
drosterone (DHEA) and monoamines in the limbic system in an itself) (Cheetham et al., 1989; Mann et al., 1989). In addition,
animal model of depression. levels of serotonin and its metabolite, 5-hydroxyundoleactic
DHEA is the most abundant adrenal androgen, functioning acid (5-HIAA), in blood and CSF of depressed patients were
also as a neurosteroid (Binello and Gordon, 2003). In recent reported to be relatively low in comparison with those
years it has been shown that DHEA has antidepressant-like observed in healthy volunteers (Asberg et al., 1984; Quan-
effects (Wolkowitz and Reus, 2003; Hsiao, 2006; Van Broekho- Bui et al., 1984; Quintana, 1992). In accordance with the
ven and Verkes, 2003; Schmidt et al., 2005; Strous et al., 2006) monoamine theory of depression, we measured the levels ofDehydroepiandrosterone and monoamines in the limbic system of a genetic animal model of childhood depression 257
serotonin and dopamine in the limbic system of “depressed” hypothalamus was surgically dissected out with forceps and frozen
prepubertal rats and their controls in order to find out whether immediately at −80 °C. The brains were then placed in a rat brain mold
the juveniles of the “depressed-like” lines show abnormal (constructed at Bar-Ilan University) on ice, and serial 0.5 mm sections
were cut and placed on chilled microscope slides. Tissue punches (Nac,
levels of monoamines as is found in depressed patients.
hypothalamus, VTA, and amygdala) were taken rapidly, using a
In the current study, we used a well-studied animal model of
stainless steel cannula with an inner diameter of 0.6 mm. The tissue
depression — the Flinders Sensitive Line (FSL). The FSL strain samples were frozen immediately at −80 °C. Extraction was achieved
was selectively bred from Sprague Dawley (SD) rats. The FSL by thawing the punches and subjecting them to probe sonication (80 W
strain is a “genetic animal model” of depression; hence, it for 5 s with a B-12 Sonifier; Branson, Danbury, CT, U.S.A.) in 0.5 ml of a
exhibits depression-like symptoms even as naïve animals perchlorate solution (0.1 M) containing EDTA/ethanol (0.02:1%) on ice.
(Overstreet, 1993; Overstreet et al., 2005; Yadid et al., 2000). A sample (100 μl) was removed for protein analysis and the rest was
FSL adult rats have been shown to demonstrate depression-like subjected to centrifugation (2000 g, 10 min, 4 °C). The resulting
symptoms such as reduced body weight and disturbed REM sleep supernatants (the tissue extracts) were filtered (0.45 μm Acrodisk;
(Benca et al., 1996; Maes and Meltzer, 1995). They also dis- Gelman, Ann Arbor, MI, U.S.A.) and stored at −80 °C until used for the
determination of both monoamines (HPLC) and DHEA (RIA).
played depression-like symptoms on several behavioral tests,
e.g., increased immobility in the swim test and greater degree
of “anhedonia” in response to chronic mild stress and acute 2.3. Analysis of monoamine content in the tissue punches
stress. The increased immobility was prevented by chronic (but
Quantitation of the 5-hydroxytriptamine (serotonin/5-HT), 5-hydro-
not acute) antidepressant treatment (Overstreet, 1993). Adult
xyundoleactic acid (5-HIAA), homovanillic acid (HVA), dopamine (DA),
FSL rats exhibited higher levels of serotonin and dopamine and 3,4-dihydroxy-phenylalanine (L-DOPA), and dihydroxyphenylacetic
its metabolites in some regions of the mesolimbic system acid (DOPAC) content of the tissue punch extracts was performed as
compared to their controls (Yadid et al., 2000). Recently, we described previously (Zangen et al., 2001). Briefly, the filtered
reported that FSL prepubertal rats exhibit increased immobility supernatants of each tissue extract were injected directly via an
in the swim test, abnormal social play as observed after 24-h of HPLC pump (Model 515, Waters, Milford, MA) onto a column (Merck
isolation and abnormal pattern of the hypothalamic–pituitary– Chemicals, Ltd; c-18, 5 μm particle size, 4.6 mm id× 250 mm, 30 °C)
adrenal (HPA) axis (Malkesman et al., 2006). coupled to an electrochemical detector (Digital Electrochemical
In the current study we attempt to determine whether Amperometric Detector, Antec-Leyden, Zeoterwoude, Netherlands),
and the oxidation potential was set to 0.76 V. The mobile phase (0.55 g
prepubertal rats of this “genetic animal model” for depres-
heptane sulphonic acid, 0.2 g EDTA, 16 ml triethylamine, 12 ml 85%
sion exhibit, in four central regions of the limbic system (Nac,
phosphoric acid, and 40 ml acetonitrile in 2 L of water; pH 2.6) was
VTA, amygdala, hypothalamus), abnormal levels of DHEA in pumped at 0.8 ml/min. Monoamine and metabolite concentrations
order to explore the potential role of neurosteroids as were expressed in relation to the protein content of the samples,
antidepressants for childhood depression. Since antidepres- which were quantified with Bio-Rad Protein Assay Kit.
sants developed to affect dopamine and serotonin levels fail
to help children suffering from depression in the same 2.4. DHEA determination
percentage as in adults (Hazell et al., 1995; Keller et al.,
2001; Kye and Ryan, 1995), and since several studies found a DHEA level was measured using a DSL 9000 Active ™ DHEA-coated tube
strong connection between serotonin, dopamine and DHEA radioimmunoassay (RIA) kit (Diagnostic Systems Laboratories, Web-
we also measured the levels of these monoamines in these ster, Tex, U.S.A.). 0.5 ml limbic region homogenates were extracted
regions in order to examine unique developmental charac- twice with 5.0 ml diethylether, centrifuged at 350 g for 5 min and
teristics in the monoamines system [We measured the kept for about 15 min at − 70 °C to allow the aqueous phase to freeze.
The etheric phase was decanted into a new glass tube, evaporated till
serotonin and dopamine levels but not noradrenaline, in an
dryness and dissolved in 120 μl of standard 0 of the RIA kit. 100 μl was
attempt to compare our prepubertal results from the current
used for the determination of DHEA (Maayan et al., 2005).
study with the adult FSL rats results reported by Yadid et al.
(2000). The connection between noradrenaline, DHEA and
2.5. Data analysis
childhood depression requires further investigation].
DHEA basal levels were analyzed by independent t-tests comparing the
2. Experimental procedures FSL and SD strains separately for each brain regions (amygdala, VTA,
2.1. Animals
SD and FSL rats were bred in our colony at Bar-Ilan University. After
weaning, juvenile rats were housed in polycarbonate cages
(38 × 21 × 18 cm.), three per cage, in a temperature controlled
vivarium (20–24 °C), under 14 h–10 h light:dark cycle (lights on at
0500).Food and water were available ad libitum.
The study protocol was approved by the Institutional Animal Care
and Use Committee and adhered to the guidelines of the Society for
Neuroscience.
2.2. Brain dissection and extraction
At the age of 34–35 days, 24 rats (4–6 of each strain) were decapitated Figure 1 Mean basal levels of DHEA (+/−SEM) of 34–35 day old
and their brains removed rapidly, and dissected as previously described SD and FSL rats. Levels in the VTA are divided by ten for
(Zangen et al., 1997; Dremencov et al., 2004). Briefly, the entire presentation purposes. ⁎p b 0.05.258 O. Malkesman et al.
Nac and hypothalamus). 5-HT, 5-HIAA and, HVA, DA, DOPA, DOPAC 4. Discussion
contents of the tissue punch extracts from each brain regions
(amygdala, VTA, Nac and hypothalamus) were analyzed by indepen-
dent t-tests comparing the FSL and their SD controls. The purpose of the current study was to examine whether
childhood depression correlates with abnormal levels of DHEA
and/or monoamines in four important regions of the limbic
3. Results system in an animal model. The results showed that FSL
prepubertal rats have lower basal levels of DHEA at least in
As evident from Fig. 1, FSL rats exhibited significantly lower some of the most important regions in the reward pathway of
levels of DHEA in both Nac [t(6) = 2.943; p b 0.05] and VTA [t(6) = the limbic system, compared to their controls. FSL rats showed
3.804; p b 0.05] compared to their control strain — SD. No sig- lower levels of DHEA both in the VTA and the Nac, compared to
nificant differences in DHEA levels were found in the other brain their control strain — SD. Several studies point to the Nac as the
regions [amygdala: t(7) = 0.722; N.S.; hypothalamus: t(10) = central region involved in, and mediating activities relating to
0.233; N.S.]. motivation, and hedonia (Phillips et al., 1991; Robinson and
The basal levels of monoamines in the different brain regions Berridge, 1993; Breiter et al., 1997). The Nac is a target of the
are presented in Fig. 2A, B, C, and D. As evident from Fig. 2A, in mesolimbic dopamine system, which arises in dopaminergic
the Nac, FSL prepubertal rats exhibited significantly higher levels neurons in the VTA of the midbrain. These VTA neurons also
of DOPAC [t(8) = 3.159; p b 0.05] and 5HIAA [t(9) = 2.715; p b 0.05] innervate several other limbic structures, including the
compared to SD rats [DOPA: t(7) = 0.59; N.S.; DA: t(10) = 0.243; amygdala and limbic regions of the neocortex (Nestler et al.,
N.S.; HVA: t(7) = 1.45; N.S.; 5HT: t(9) = 0.373]. In Fig. 2B, one can 2002). Though not much is known about the activity of the
see that there were no significant differences in the VTA between neurosteroid DHEA in the brain (Goodyer et al., 2001), it was
the FSL rats and their controls [DOPA: t(4) = 1.41; N.S.; DA: t(5) = recognized as having potential applications in the treatment of
2.31; N.S.; DOPAC: t(6) = 0.42; N.S.; HVA: t(4) = 1.85; N.S.; 5HT: depression (Binello and Gordon, 2003; Wolkowitz and Reus,
t(6) = 0.43; N.S.; 5HIAA: t(5) = 0.233]. In the hypothalamus, as 2003). The antidepressive effect of DHEA can be explained, as
evident from Fig. 2C, FSL showed significantly lower levels of: mentioned earlier, by the interaction between the sigma 1
HVA [t(6) =2.866; p b 0.05] and 5HIAA [t(8) = 3.993; p b 0.01] receptor agonist DHEAS (Maurice et al., 1996) and noradren-
compared to the SD prepubertal rats [DOPA: t(8) = 0.92; N.S.; aline and serotonin neurotransmission. Enhancement of se-
DA: t(6) = 1.34; N.S.; DOPAC: t(6) = 0.489; N.S.; 5HT: t(5) = rotonin (Delgado, 2000) neurotransmission is considered to
1.128; N.S.]. As can be noticed in Fig. 2D, there were no have an antidepressant effect. Since DHEA has an antidepres-
significant differences in the amygdala between FSL and SD sant-like effect (Binello and Gordon, 2003; Wolkowitz and
prepubertal rats [DOPA: t(5) =1.53; N.S.; DA: t(7) = 0.515; N.S.; Reus, 2003), lower levels of DHEA in two important regions in
DOPAC: t(5) = 1.9; N.S.; HVA: t(4) = 1.155; N.S.; 5HT: t(6) = 1.4; the limbic system of the FSL rats may contribute to “depression
5HIAA: t(6) = 1.48; N.S.]. like” symptoms found in the prepubertal rats of this line, such
Figure 2 (A) Mean basal levels of monoamines and their metabolites in the Nac (+/−SEM) of 34–35 day old FSL and SD rats. Levels of
DA, DOPAC, HVA, are divided by ten for presentation purposes. ⁎p b 0.05. (B) Mean basal levels of monoamines and their metabolites in
the VTA (+/−SEM) of 34–35 day old SD and FSL rats. Levels of DOPA, DA, are divided by ten for presentation purposes. (C) Mean basal
levels of monoamines and their metabolites in the hypothalamus (+/− SEM) of 34–35 day old SD and FSL rats. Levels of DOPA, DA, DOPAC,
HVA, 5HIAA, are divided by ten for presentation purposes. ⁎p b 0.05; ⁎⁎p b 0.1. (D) Mean basal levels of monoamines and their metabolites
in the amygdala (+/−SEM) of 34–35 day old SD and FSL rats. Levels of DOPA are divided by ten for presentation purposes.Dehydroepiandrosterone and monoamines in the limbic system of a genetic animal model of childhood depression 259
as increased immobility time in the forced swim test and 1999; Yadid et al., 2000), prepubertal FSL rats in the current
abnormal social play (Malkesman et al., 2006). study exhibited higher levels of only a few monoamines
As mentioned earlier, administration of DHEA increases metabolites in the Nac (but not in the VTA and amygdala).
serotonin levels in the hypothalamus (Abadie et al., 1993; Svec Specifically, Zangen et al. (1997) and Yadid et al. (2000)
and Porter, 1997) and Nac (Maayan et al., 2005), and treatment reported that adult FSL rats exhibited higher levels of 5HT,
with DHEA increased the dopamine content in the VTA and the 5HIAA, dopamine, DOPAC and HVA in the hypothalamus and
Nac (Maayan et al., 2006), in adult rats. In the present study the Nac, compared to their SD controls; while in the current
we found that the prepubertal FSL rats had lower levels of the study, prepubertal FSL rats exhibited only higher levels of
dopamine metabolite HVA. We did not find a significant 5HIAA in the Nac and lower levels of HVA and 5HIAA in the
difference in hypothalamic serotonin levels between the hypothalamus compared to their SD controls. These different
“depressed-like” rats and their controls, but in this region, abnormal monoamine patterns between the “depressed”
the FSL prepubertal rats exhibited lower levels of the serotonin prepubertal rats and their adults, may help to explain why
metabolite, 5HIAA, compared to controls. Since it is known depressed children and adolescents fail to respond to
that there are anatomical connections between the VTA and antidepressant treatment as well as adults do (Hazell et al.,
the hypothalamus and vice versa, e.g. projections of dopa- 1995; Keller et al., 2001). On the other hand, FSL prepubertal
mine, and acetylcholine (Rada et al., 2000), these results may rats exhibited the same pattern of abnormal DHEA basal
suggest that the low levels of DHEA found in the VTA and Nac of levels as was found in adult FSL rats (Maayan et al., 2005).
the “depressed” rats may have some negative effects on brain In sum, the results suggest that a putative genetic animal
serotonin and dopamine, potentially reflecting decreased model of childhood depression, the prepubertal FSL rat,
metabolism of serotonergic and dopaminergic neurons in exhibited abnormal levels of DHEA (as in adult FSL rats) and
these structures, as found in other studies (Abadie et al., monoamines (different pattern than adult FSL rats) in various
1993; Svec and Porter, 1997). This may support a potential role regions of the limbic system. The difference in abnormal
for neurosteroids as antidepressants for childhood depression. monoamine patterns between the “depressed” prepubertal
Several studies have shown that DHEA behaves like an rats found in the current study, and in adults (found in several
antiglucocorticoid by counteracting the effects of cortico- studies, Zangen et al., 1997, 1999; Yadid et al., 2001) may
sterone (Hechter et al., 1997). However, in a previous study represent the biological basis for why depressed children and
from our lab, 35-day-old FSL rats displayed “ hypocortiso- adolescents fail to respond to antidepressant treatment in
lism” — lower basal levels of plasma corticosterone and contrast to adults (Hazell et al., 1995; Keller et al., 2001),
adrenocorticotropic hormone (ACTH) — (Malkesman et al., and might imply that other non-monoaminergic factors, such
2006). Although the results regarding the “hypocortisolism” as DHEA contribute to childhood depression (Possel and
exhibited by the prepubertal FSL rats and the results from Hautzinger, 2006).
the current study might not fit the findings of these previous Taking in consideration former results suggesting an
studies (Hechter et al., 1997), it is important to mention that antidepressant-like effect of DHEA in adult rats of a “depres-
secretion of cortisol/corticosterone and DHEA(s) are regu- sive-like” strain (Maayan et al., 2005) and humans (Schmidt
lated by ACTH, there may be dissociation between these et al., 2005) and our current data, it is possible that treatment
hormones, e.g., during (chronic) stress or medical illness with this neurosteroid may be a promising novel therapeutic
(Parker et al., 1985), and DHEA levels can be regulated option for depressed adults and (while closely monitoring
independently of cortisol/corticosterone (Herbert et al., sexual maturation and androgenic effects; for review see
1996). In addition, Nac DHEA, measured in the current study, Binello and Gordon, 2003) especially for depressed children
takes no obvious part in the HPA axis. and adolescents who fail to respond to the available mono-
The pattern of results regarding the basal levels of aminergic antidepressant treatments.
monoamines in the limbic system suggests that FSL prepuber-
tal rats show some serotonergic and dopaminergic abnormal-
Role of the funding source
ities in some regions of the limbic system. In the Nac, one of
the main areas responsible for control of locomotion, Funding for this study was provided by a grant for the Israel Science
motivation and reward, and response to antidepressants Foundation (ISF) to Aron Weller; the ISF had no further role in study
(Yadid et al., 2001), the FSL rats had higher levels of DOPAC design; in the collection, analysis and interpretation of data; in the writing
and 5HIAA, compared to their controls. It is known that the of the report; and in the decision to submit the paper for publication.
major degradation product of 5HT, 5HIAA, is found in the
cerebrospinal fluid (CSF) as well as in the brain itself (Van Contributors
Praag, 2004). Both animal (Mignot et al., 1985) and human
(postmortem) studies (Stanley et al., 1985) have revealed a Oz Malkesman designed the study, conducted most of the procedures
close correlation between brain and CSF 5HIAA. Lowered CSF and wrote the manuscript. Yoram Braw conducted the monoamine
5HIAA in depression was shown to correlate positively with and the DHEA measurements. Edward Ram helped with the brain
increased anxiety (Van Praag, 2004). dissections and the DHEA measurements. Rachel Maayan helped to
conduct the DHEA measurements, performed in her lab, with her
The higher levels of the serotonin metabolite found in the
guidance and under her supervision. Avi Weizman helped to design
Nac of the prepubertal FSL rats in the current study are in
the study protocol and the DHEA determination. Noa Kinor,
accordance with the abnormal levels of this metabolite, monoamines measurement expert, guided and helped in conducting
reported previously in adult FSL rats (Yadid et al., 2000). these measurements and in their interpretation. Gal Yadid helped to
However, while adult FSL rats exhibited in a previous study in design the study protocol, conducted the brain dissection and
our lab higher levels of all the monoamines and their extraction. Aron Weller helped to design and write the study
metabolites (in Nac, hypothalamus; Zangen et al., 1997, protocol, attain approval and funding for the project and co-edited260 O. Malkesman et al.
the manuscript. All authors contributed to the study and have cortex through activation of dopamine D1 and sigma-1 receptor.
approved the final draft of the manuscript. Neuropharmacology 52 (3), 966–974.
Dorn, L.D., Dahl, R.E., Brimaher, B., 1997. Baseline thyroid hormones
in depressed and non-depressed pre- and early-pubertal boys and
Conflict of interest girls. J. Psychiatr. Res. 31, 555–567.
Dranovsky, A., Hen, R., 2006. Hippocampal neurogenesis: regulation by
All authors declare that they have no conflicts of interest.
stress and antidepressants. Biol. Psychiatry 59 (12), 1136–1143.
Dremencov, E., Gispan-Herman, I., Rosenstein, M., Mendelman, A.,
Acknowledgements Overstreet, D.H., Zohar, J., Yadid, G., 2004. The serotonin–
dopamine interaction is critical for fast-onset action of antide-
pressant treatment: in vivo studies in an animal model of
The research reported in this paper was completed as part of the first
depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 28
and second authors' Ph.D. dissertations, in the Interdisciplinary Program
(1), 141–147.
in the Brain Sciences and the Department of Psychology (respectively),
Dubrovsky, B.O., 2005. Steroids, neuroactive steroids and neuro-
Bar-Ilan University, Ramat-Gan, Israel. OM and YB were supported by
steroids in psychopathology. Prog. Neuro-Psychopharmacol. Biol.
President's fellowships, Bar-Ilan University. The authors thank Dr. David
Psychiatry 29 (2), 169–192.
Overstreet for his assistance. This work was supported by a grant from
Duman, R.S., Monteggia, L.M., 2006. A neurotrophic model for stress-
the Israel Science Foundation to A. Weller. Work in A. Weller's lab is
related mood disorders. Biol. Psychiatry 59 (12), 1116–1127.
partially supported by the Paula Rich Foundation.
Elhwuegi, A.S., 2004. Central monoamines and their role in major
depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 28,
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