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Background: Forced swimming test (FST) is an animal model which evaluates behavioral despair and the effect of antidepressants such as the selective serotonin reuptake inhibitors; the FST modifies the expression of some receptors related to antidepressant response, but it is not known whether serotonin transporter (SERT), their main target, is affected by this test in animals of different ages. Antidepressant response has shown age-dependent variations which could be associated with SERT expression. The aim of the present study was to analyze changes in the SERT immunoreactivity (SERT-IR) in dorsal raphe and lateral septum of male rats from different age groups with or without behavioral despair induced by their exposure to the FST, since these two structures are related to the expression of this behavior. Methods: Prepubertal (24 PN), pubertal (40 PN), young adult (3–5 months) and middle-aged (12 months) male rats were assigned to a control group (non-FST) or depressed group (FST, two sessions separated by 24 h). Changes in SERT-IR in dorsal raphe and lateral septum were determined with immunofluorescence. Results: Pubertal and middle-aged rats showed higher levels of immobility behavior compared to prepubertal rats on the FST. SERT-IR showed an age-dependent increase followed by a moderate decrease in middle-aged rats in both structures; a decreased in SERT-IR in lateral septum and dorsal raphe of pubertal rats was observed after the FST. Conclusions: Age differences were observed in the SERT-IR of structures related to behavioral despair; SERT expression was modified by the FST in lateral septum and dorsal raphe of pubertal rats. Keywords: Despair, Forced swimming test, Rats, Serotonin transporter, Age differences Background proposed that SERTs are the primary regulators of the Serotonin transporter (SERT) is responsible for termi- serotonergic transmission and that the effect of SSRIs nating the serotonin (5-HT) action in the extracellular may be related with their number . space by its reuptake into presynaptic terminal, control- Serotonin regulation shows age-dependent adapta- ling the availability of this neurotransmitter in the syn- tions; 5-HT uptake measured in animal studies is higher aptic cleft . This protein is the main target of the in the developing brain as compared with adult values selective serotonin reuptake inhibitors (SSRIs), which . In rats mRNA for SERT can be determined by em- bind SERT blocking its activity; this action allows an in- bryonic day 13, and the uptake of 5-HT reaches adult crease in 5-HT levels in the synaptic cleft and in seroto- levels at birth in brain synaptosomes, at five weeks of nergic neurotransmission, being this first step for the age the amount of uptake is doubled and then decreases antidepressants’ long-term effect [2,3]. Several authors to adult levels again . Specific areas, such as the me- dian raphe exhibit a 25% decrease of SERT density in * Correspondence: firstname.lastname@example.org adults compared to prepubertal rats . SERT binding Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada in 3 to 18 years old children and adolescents shows an México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, Mexico City 14370, Mexico Full list of author information is available at the end of the article © 2014 Ulloa et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. Ulloa et al. Behavioral and Brain Functions 2014, 10:3 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/10/1/3 increase , followed by a decrease at the approximate n = 9) and middle age (12–14 months; weight 600 g, rate of 10 percent per decade . n = 8), considering as a reference the reproductive status SERT can be modified by stress, where a reduction of in these ages . All experimental procedures were per- mRNA in the raphe pontis was observed . FST is an formed in accordance to general principles of laboratory extensively used model in which a behavioral change is animal care  and the Mexican official norm for ani- induced by acute stress: After a pretest 15-min session, mal care and handling (NOM-62-ZOO-1999) . The rodents show an increased immobility 24 h later in the experimental protocol with laboratory animals was elab- 5-min test. The increased immobility reflects despair, a orated taking into account the 3R principles, and was depressive-like behavior , which is reduced by anti- approved by the ethical committee of Instituto Nacional depressant drugs [12,13]. A 5-min session significantly de Psiquiatría Ramón de la Fuente Muñiz (NC093370.1). increases the 5-HT output in the median raphe nuclei ; more recently, it was demonstrated that the FST Experimental design increases membrane potential excitability and regulates Animals were randomly assigned to FST or control group the modulation of glutamatergic afferents on dorsal ra- (non-FST groups, 4 subjects per group). Thirty minutes phe neurons, these changes could alter their ability to after the second session of FST, rats were anesthetized process incoming signals and distribute them to their and perfused and their brains were removed and pre- distinct forebrain targets . Dorsal dorsal raphe sends served. The control animals remained in the same housing projections to lateral septum . In FST, the discharge and care conditions and perfused at the same time than rate of serotoninergic neurons in dorsal raphe was atten- the FST group. uated by the CRH of local GABAergic neurons . In lateral septum, a 5-HT decrease after pretest followed by an increase after the test session have been related with Forced swimming test despair , thus immobility was positively correlated For this study the modified version of the FST was used and swimming was negatively correlated with changes in . Swimming sessions were conducted by placing rats extracellular 5-HT in this structure . In addition, an in individual glass cylinders (46 cm height × 20 cm dia- attenuated and enhanced firing rate in lateral septum meter) containing water at 23-25°C, 30 cm deep. Groups was related with despair and the response to antidepres- assigned to FST were subjected to the 15 min pre-test sants, respectively . followed by a 5 min test 24 h later, which was videotaped. Numerous evaluations of fluoxetine (an SSRI) have re- The sessions were run between 1200 and 1400 h. A time- vealed an optimal antidepressant response in young adult sampling technique was used to score, every 5 s, the pre- male rats which is not observed in other ages, i.e., pre- sence of immobility (floating without struggling and pubertal rats show no antidepressant-like response in the making only those movements necessary to keep the forced swimming test (FST) while aged rats exhibit an head above the water), swimming, active motions (moving attenuated antidepressant-like effect [21,22]. These var- and diving around the jar) or climbing (active movements iations may be explained by age-dependent changes on with forepaws in and out the water, usually directed SERT expression which could account for the variations against the wall). Results were expressed as mean number on its susceptibility to be affected by stress. of counts ± s.e.m. of the behaviors each 5 min. Inter- and With this basis, the aim of the present study was to intra-rater reliability was at least r = 0.87 for scoring FST analyze changes in the SERT immunoreactivity (SERT-IR) behaviors by two observers. in dorsal raphe and lateral septum of control or FST sub- mitted male rats from different age groups. Open field test (OFT) Methods An ambulation test was conducted in order to discard Animals an influence of locomotor activity on the results of the Male Wistar rats from the vivarium of the Instituto FST. Independent groups of prepubertal, pubertal, young Nacional de Psiquiatría Ramón de la Fuente Muñiz were adults, and middle aged male rats (n = 10 per group) housed 4–8 per cage in polycarbonate boxes according were evaluated in an automatic system (PanLab) consist- to age on an inverted 12-h light/dark schedule in a ing of a Plexiglass cage (45×35×45 cm) with two infrared temperature-controlled (22°C) room. All animals had sensors located on the cage walls (2.5 and 10.5 cm from ad-libitum access to food and water. The rats were clas- the cage base), coupled to IR LE8811 software. The sys- sified by age in prepubertal (24–32 PN, weight 90 g, tem detected all rats’ ambulatory movements and regis- n = 7), pubertal (40–41 PN, considering preputial separ- tered the movement numbers (counts) in a 5-min test. ation to distinguish the onset of pubertal age; weight The results of ambulatory activity were expressed as 120 g, n = 8), young adult (3–5 months; weight 370 g, mean ± s.e.m. Ulloa et al. Behavioral and Brain Functions 2014, 10:3 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/10/1/3 Perfusion threshold was established to eliminate non-specific fluo- After FST (or under control condition) rats were anes- rescence, pixels with fluorescence intensity above the thetized with ketamine (100 mg/kg, i.p., Indoketam® threshold were considered specific for SERT-IR. The 1000, Virbac) and xilazine (20 mg/kg, i.m., Rompun®, threshold (mean + 2.5 standard deviations) used in all Bayer) and perfused with a phosphate buffer solution preparations was established from 20 images of mid- (PBS:NaCl0.13M;NaH PO 0.003 M; Na HPO dle-aged animals brain structures. In these samples the 2 4 2 4 0.007 M) and heparine (1 mL per liter of PBS; Inhepar®, referred threshold value effectively discarded background Pisa) followed of 4% paraformaldehyde in PBS. Brains fluorescence. Once eliminated on specific fluorescence, were removed, washed in PBS and preserved at 4°C in the pixels with SER-IR were quantified and expressed as 30% sucrose and 0.1% timerosal in PBS. Afterwards, brain percentage relative to total pixels in the analyzed area tissue was cut in a cryostat (−22°C, Microm HM 505 N) (relative SERT-IR). This parameter was considered as an into coronal sections at 40 μm thick, which were pre- indicator of SERT expression. The parameters (illumin- served in a 30% sucrose and 0.1% timerosal in PBS at ation device: 488, slit 30 nm; time of exposure: 200 msec; 4°C . gain: 100; and binding: 2) used to digitalize the images and the region of analysis (size: 670 × 512 pixels; area: 343040 Immunofluorescence pixels ) were constant across experimental groups and SERT-IR was examined on four animals from each group. brain structures. A similar image analysis was used for Brain sections containing lateral septum (Bregma −0.24 other research groups to quantify proteins expression mm) and dorsal raphe (Bregma −4.56) were identified fol- [28,29]. Quantification of SERT-IR was carried out bila- lowing the Paxinos and Watson Atlas for rat brain . terally in the dorsal, intermediate and ventral portion of Four adjacent sections of each area were taken for deter- lateral septum, meanwhile in the raphe nuclei only dor- mination of SERT-IR. Brain sections were washed with sal raphe was analyzed. PBS and nonspecific sites were blocked by incubation with solution A: a PBS solution containing 10% goat serum, Statistical analysis 1% bovine serum albumine (BSA, Research Organics) Influence of age in the FST and OFT behaviors was ana- and 0.3% Triton TX-100 (Sigma-Aldrich). Sections were lyzed with a one-way ANOVA followed by a Tukey’s test placed in box and incubed for 1 h at room temperature when variance analysis attained statistical significance under constant stir with the primary monoclonal anti- (p < 0.05). The relative SERT-IR area percentage was an- body against the 1–85 a.a. N-terminal of the SERT, de- alyzed with a three-way ANOVA, considering the con- veloped in mouse (Chemicon International) at a 1:500 ditions of stress (control or FST), structure and age, dilution in solution A. Later, slides were incubated at 4°C followed by a Tukey’s test. When it was necessary, pairs constantly stirred overnight and later washed with 0.15% of groups were compared with a Student t test. Triton TX-100 in PBS (Solution B). Brain sections were incubated at room temperature for 2 h with the secondary antibody (anti-IgG of mouse done in goat) marked with Oregon green 488 (Invitrogen®, Molecular Probes) dilution 1:100 in PBS with 5% goat serum and 0.3% Triton TX-100. Slides were washed with solution B, and mounted in a dark room on slides using antifade resin (Invitrogen®, Molecular Probes). Quantification of SERT immunoreactivity A semiquantitative method was used to determine ex- pression of SERT. Immunofluorescence was observed in a 40X oil immersion objective (SFluor, NA 1.3 Nikon) in an inverted microscope (Nikon Diaphot 300) equipped with an epifluorescence system (excitation: 480 ± 15 nm; dicroic mirrow: 505 nm; emission: 535 ± 20 nm) and coupled to a Xenon arc lamp (75 W). Images of SERT- IR were captured with a digital CCD camera (ORCA- ERC4742-95, Hamamatsu) and analyzed with the software MetaFluor version 6.1 (Universal Imaging Corporation). Figure 1 FST behaviors of male rats in the 5-min session. For each digitalized image a frequency histogram of fluo- *p < 0.05, **p < 0.01 results of Tukey’s test vs. prepubertal rats. rescence intensity was generated: in this histogram a Ulloa et al. Behavioral and Brain Functions 2014, 10:3 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/10/1/3 Table 1 Ambulatory activity of male rats in a open Results field test FST Number of counts/5 min In the test session statistical analysis showed differences in immobility behavior (F = 4.605, p = 0.01). Pubertal Groups 3,28 and middle-aged rats showed higher levels of immobility Prepubertal 786.60 ± 47.00 behavior compared to prepubertal rats. No significant *** Pubertal 1640.90 ± 84.50 differences were found in immobility of pubertal, adult *** Adult 1701.80 ± 108.30 and middle-aged rats. In addition, no significant variations ***,# Middle-aged 1341.60 ± 96.99 in the expression of swimming (F = 1.65, p = 0.20) 3,28 Results of the Turkey’s test: ***p < 0.001 vs. prepubertal rats, p < 0.05 vs. and climbing (F = 2.64, p = 0.06) was found (Figure 1). 3,28 Adult. OFT Statistical analysis showed differences in locomotor ac- tivity (Table 1, F = 22.948, p < 0.001). Prepubertal rats 3,36 Figure 2 Representative images of photomicrographs of SERT-IR in lateral septum of male rats. Comparison between prepubertal, pubertal, adult and middle aged males subjected to FST vs. non-FST groups. The field of analysis is indicated in the upper slide (modified of Paxinos and Watson ). Ulloa et al. Behavioral and Brain Functions 2014, 10:3 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/10/1/3 had lower levels of ambulatory activity in this test in (Figure 2). Analysis of relative SERT-IR quantified from comparison to the other groups. Ambulation was stabi- the lateral septum and dorsal raphe of all animals showed lized in pubertal and young adults and decreased in the a main effect of age (F = 4.284, p = 0.009) and brain 3,48 middle-aged group, this response attained statistical sig- structure (F = 25.56, p < 0.001) but not significant 1,48 nificance respect to young adults. changes determined by stress (F = 0.39, p = 0.53), or 1,48 the interaction between those factors (stress × age: F = 3,48 SERT-IR 0.744, p = 0.058; stress × region: F = 0.267, p = 0.608; 1, 48 Figures 2 and 3 show photomicrographs of SERT-IR in age × region: F = 0.199, p = 0.331 and stress × age × re- 3,48 lateral septum and dorsal raphe, under control and FST gion: F = 0.744, p = 0.531). Post-hoc analysis indicated 3,48 conditions. Independently of age and stress condition, that young adult rats showed larger relative SERT-IR than dorsal raphe exhibited fine and short punctuated fibers prepubertal (p = 0.036) and pubertal rats (p = 0.012). The with varicosities (Figure 3). In contrast, lateral septum fi- dorsal raphe showed larger SERT-IR than lateral septum bers were scarce but longer and wider than dorsal raphe’s (p < 0.001). Figure 3 Representative images of photomicrographs of SERT-IR in dorsal raphe of male rats. Comparison between prepubertal, pubertal, adult and middle aged males subjected to FST vs. non-FST groups. The field of analysis is indicated in the upper slide (modified of Paxinos and Watson ). Ulloa et al. Behavioral and Brain Functions 2014, 10:3 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/10/1/3 Since the interaction stress × age tended to be statisti- active behaviors than the adults no significant age-related cally different (p = 0.058), we decided to evaluate relative changes were observed. SERT-IR differences determined by stress on each struc- Acute stress is used in animal models to induce behav- ture and for a single age. Differences by stress were ob- ioral, physiologic and neural changes relative to human served on each structure, in lateral septum prepubertal depression . The modified version of the FST  is subjects with FST showed a larger immunoreactive area a model that includes a pre-test session required to in- than non-FST rats (t = −2.77, p = 0.032). In contrast, pu- duce despair, reflected as an increase of immobility and bertal rats without FST exposure showed larger SERT-IR a decrease of active behaviors in the test session [31,32]. than the FST group in lateral septum (t = 4.60, p = 0.004) The current study confirms the behavioral changes re- and dorsal raphe (t = 3.03, p = 0.02.) (Figure 4). No dif- ported in adult rats and evidences a similar behavioral ferences were found between relative SERT-IR of FST profile for prepubertal animals. The only study which and non-FST groups of young and middle-aged adult rats. evaluated the ontogeny of behaviors evaluated in the FST followed rats from 14 PN to 30 PN and reported that immobility emerges at day 21 PN and stabilizes be- Discussion ginning at day 26 PN . To our knowledge, there are Present results show that immobility behavior in the no studies examining immobility behavior from puberty; FST can be displayed by rats of different ages. Pubertal present results show that adult immobility levels are and middle-aged rats were more sensitive to the effects reached at puberty and stabilized from 40 days to 12 of forced swimming and showed increased levels of im- months since animals exhibited non significant varia- mobility respect to prepubertal and young adults. This tions (pubertal +36.24%, adult +22.81% and middle-aged study followed the methods described by Detke , rats +29.53%, respect to prepubertal). The influence of bo- where active behaviors (swimming and climbing) were dy weight could be discharged since behavior of adult measured, although younger animals displayed more males did not differ from pubertal ones, despite that the former group is almost 200% heavier than the later. Another possible explanation for the differences on immo- bility could be related with an age-dependent reduction of locomotor activity ; however, present results in the OFT contradict this idea, given that animals with lower ambulation (i.e. prepubertal ones) showed reduced immo- bility in the FST; in turn, middle-aged and young adult rats expressed similar immobility, but the former group showed reduced ambulation. It can be argued that the developmental related chan- ges in serotonergic system influence directly the observed changes on immobility in rats of different ages. Gallineau and colleagues showed that SERT density measured in dorsal raphe and parietal cortex peaks and declines prior to PN 20, these changes were suggested to be secondary to a peak in extracellular 5-HT during brain development . To our knowledge, there are no studies examining lifespan SERT-IR in rodents, thus present results showed a pubertal and adulthood increase followed by a moderate decline in middle age. In this line, a radiobinding study in non-human primates have shown that aging is associated with a SERT specific binding decrease, which was related to the hyperactivity of Hypothalamus-Pituitary-Adrenal axis . Present results suggest that FST reduces SERT-IR in lateral septum of pubertal rats, which could be related to the higher expression of immobility observed in these Figure 4 Quantification of SERT-IR in lateral septum (upper animals. A 5-HT decrease in lateral septum after pretest graph) and dorsal raphe (lower graph). Data are expressed as was related to behavioral despair , which is pre- mean ± SEM. Results of t test: *p < 0.05, **p < 0.01 groups subjected vented by fluoxetine . Changes in the lateral septum to FST vs. non-FST (control). SERT-IR could be secondary to 5-HT concentration or Ulloa et al. Behavioral and Brain Functions 2014, 10:3 Page 7 of 8 http://www.behavioralandbrainfunctions.com/content/10/1/3 changes in the transcription . Previous studies of Authors’ contributions REU and LMM designed the study and drafted the manuscript, ADV and JHP Lucki et al. suggested that changes FST induces CRH re- carried out the behavioral tests and immunofluorescence technique, MLO lease on 5-HT neurons of dorsal raphe; this peptide act- supervised the immunoassays and the elaboration of the figures. All authors ing through CRF2 receptors reduces discharge rate of reviewed and approved the final manuscript. dorsal raphe neurons, which send projections to lateral Acknowledgements septum; specifically, the dorsal dorsal raphe has a func- The authors wish to thank Miss Gabriela Lopez for her assistance in the tional relationship with lateral septum, and modulates preparation of manuscript and Sergio Márquez-Baltazar for animal caring. 5-HT levels in lateral septum. This neurochemical change This work was supported by Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz (NC093370.1). could be directly related to immobility . Studies have revealed an age- and androgen-dependent regulation of Author details CRF2 binding in rat intermediate lateral septum, showing Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Calzada México-Xochimilco 101, Col. San Lorenzo Huipulco, Delegación Tlalpan, an increased functionality from puberty to adulthood . Mexico City 14370, Mexico. Hospital Psiquiátrico Infantil “Dr. Juan N Based on this idea, present results show that prepubertal Navarro”, San Buenaventura 86, Col. Belisario Domínguez, Delegación Tlalpan, animals exhibit less depressive-like behaviors and more Mexico City 14080, Mexico. SERT expression than pubertal animals. According to Received: 8 August 2013 Accepted: 28 January 2014 Blakely’s hypothesis , the regulation of the transporter Published: 3 February 2014 protein in the presynaptic membrane is more dependent on the concentration of serotonin in the synapse than References 1. Hensler J: Serotonin in mood and emotion. In Handbook of the behavioral driven by gene expression according to the “use it or lose neurobiology of serotonin. Edited by Müller C, Jacobs B. San Diego: it”, so our results could suggest that 5-HT levels are Academic Press; 2010. higher in prepubertal animals, leading to a higher expres- 2. 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Behavioral and Brain Functions – Springer Journals
Published: Feb 3, 2014
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