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JUSTEL, NADIA; BENTOSELA, MARIANA; MUSTACA, ALBA; RUETTI, ELIANA NEONATAL TREATMENT WITH CLOMIPRAMINE AND DEPRESSION: A REVIEW OF BEHAVIORAL AND PHYSIOLOGICAL FINDINGS Interdisciplinaria, vol. 28, núm. 2, julio-diciembre, 2011, pp. 207-220 Centro Interamericano de Investigaciones Psicológicas y Ciencias Afines Buenos Aires, Argentina

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NEONATAL TREATMENT WITH CLOMIPRAMINE AND DEPRESSION: A REVIEW OF BEHAVIORAL AND PHYSIOLOGICAL FINDINGS*

NADIA JUSTEL**, MARIANA BENTOSELA***, ALBA MUSTACA**** AND ELIANA RUETTI*****

*This work was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT- PICT 25335), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET - PICT 38020) and Universidad de Buenos Aires (UBA - UBACyT P002). **Psychologist. Doctoral Position in Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). E-Mail: [email protected] ***Doctor in Psychology. Researcher of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). E-Mail: [email protected] ****Doctor in Psychology. Professional Technician in Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). E-Mail: [email protected] *****Doctor in Psychology. Researcher of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). E-Mail: [email protected] Laboratorio de Psicología Experimental y Aplicada (PSEA). Instituto de Investigaciones Médicas (IDIM). CONICET-UBA. Combatientes de Malvinas 3150 (C1427ARO) Ciudad Autónoma de Buenos Aires. República Argentina.

RESUMEN pueden estudiarse los mecanismos cerebrales implicados en la patogénesis y tratamiento del El presente trabajo describe los principales trastorno que por razones éticas son impensables resultados acerca de un nuevo y probable mo- de llevar a cabo en humanos. Por ello, se consi- delo animal de depresión. Este modelo se basa, dera de gran valor el estudio realizado con el paradójicamente, en la administración de un an- modelo de clomipramina con la perspectiva de tidepresivo, clomipramina, a ratas neonatas. que se siga trabajando en la validación del Cuando los animales alcanzan la adultez, mues- mismo. tran alteraciones comportamentales que pueden ser interpretadas como depresivas, como hipe- Palabras clave: Depresión; Clomipramina; Tra- ractividad, descenso en la búsqueda de placer, tamiento neonatal; Ratas. anormalidades en el sueño, entre otras. Se ana- lizan los posibles mecanismos neurofisiológicos y neuroendocrinos involucrados. A pesar de las ABSTRACT limitaciones que ofrece un modelo animal, es importante cómo logra reproducir algunos sínto- Many times in science, the discovery of a mas hallados en la depresión y debido a esto las treatment that has certain effect happens acciden - ventajas del mismo son invaluables. Además, tally while the scientists are investigating another

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phenomenon. This is the case of the discovery of circulating corticosterone increases less and a possible animal model of depression by the returns more rapidly to basal levels than administration of clomipramine (CLI) during control groups. For this reason, we can neonatal days. Adult animals exposed to CLI in conclude that if alterations in the HPA axis neonatal days showed alterations in REM indeed exist in CLI - treated animals, it is still sleep (for example, the decrease of REM unclear in which way the deregulation is latency); lower weight, disruptions in loco - manifested. Other results support the hypoth- motor activity (the increase in activity depend esis that alterations found in CLI - treated on the dark / light phase in which the test animals are due to alterations in sero toni - starts, when the animals were tested in the nergic transmission during a critical period of light phase they found increase in activity, but development, such as the neonatal stage; more no changes were observed when the animals specifically, a reduction in the hypothalamic were tested in the dark phase); less intra- concentration of serotonin, like a decrease in craneal self-stimulation, lower saccharin and the neuronal firing in the dorsal raphe nu - sucrose consumption, less suppression of the cleus. An increase in cholinergic activity was consummatory behavior, sexual alterations in also found, although the data in this field is males (for example, expressed as a lower not as vast as that found in relation to the number of mounts and ejaculations; no neurotransmission of serotonin. All of these alterations were found in the activity of the results suggest that rats treated with CLI Hypothalamic - Pituitary - Gonadal axis and during neonatal days present alterations in the level of testosterone was normal), higher adulthood analogous to human depression, alcohol consumption, disruptions in the ago - however other findings indicate that is not yet nis tic response (CLI - treated animals were a valid model. Further research is needed, and significantly less aggressive than control we have to be cautious with the conclusions groups) and in learning (in the passive because there is some evidence suggesting avoidance task and 8 radial arm maze) that this is a promising model but other does compar ed to untreated animals (rats that not support its validity. If a model like the received vehicle during neonatal days). neonatal adminis tration of CLI achieves the Several of these abnormalities could be reproduction of some symptoms, neurophy- reversed with those treatments that are siological and behavioral alterations of de- effective for treating depression in humans pres sion, the advan tages are invaluable. In (antidepressive drugs, nicotine and REM this sense, neonatal treatment with CLI is a sleep deprivation treatment). These results very promising animal model for the study of were obtained in male rats of different strains depression. and in hamsters, and at different months, the majority of them at 3-4 months, and some of Key words: Depression; Clomipramine; Neo- them after the sixth, this could be because natal treatment; Rats. some changes were caused with the decre - ment in the age of the animals, although further research is needed to elucidate this issue. Neuroendocrinal alterations analo gous to those found in human depression were also discovered in CLI - treated rats, although the Many times in science, the discovery of a data is contradictory. These include Hypo- treatment that has a certain effect happens ac- thalamic - Pituitary - Adrenal axis alterations; cidentally while the scientists are investi gat- while it is true that some experimental results ing another phenomenon. This is the case of found that CLI - treated rats have a higher the discovery of a possible animal model of basal level of corticosterone than controls, depression by the administration of clomi - others found that not only do they differ in pramine (CLI) during neonatal days. With the basal level, also during the stress situation; aim of studying the REM sleep function in the

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ontogenetic development of the animals, neo - agitation of depression and the alterations in natal rats were deprived of REM sleep REM sleep could be similar to the decrease through the daily administration of a powerful in the latency for entering REM sleep found suppressor of it: CLI (Mirmiran, van de Poll, in this type of disorder. Corner, de Boer, & van Oyen, 1980; These findings could be interpreted as in- Mirmiran, van de Poll, Corner, van Oyen, & dicators that REM sleep during the neonatal Bour, 1981). This drug is a reuptake inhibitor period plays an important role in the develop- of serotonin and nor adrenaline. In these stud- ment of sleep and of normal behavior in later ies, the hypothesis is that the suppression of stages of life (Mirmiran et al., 1980, 1981, REM sleep could affect the normal develop- 1983), or could be interpreted as marked al- ment of the animal. At the moment, other dif- terations of a mood disorder, more specifical - ferences in the development of subjects ly, endogenous depression, known today as treated with CLI compared to their control Major Depressive Disorder (Feng, Guan, groups (animals which received vehicle in- Yang, & Fang, 2003; Vogel, G. & Vogel, F., stead of CLI during the same period of life) 1982), but this later statement could be only were not identified. However, in adulthood justified by clinical evidence. In conclusion, CLI - treated rats presented ab nor mal ities in the pattern of these abnormalities suggests that sexual behavior, locomotor activity and other neonatal treatment with CLI could be consid- behaviors. The experimental animals showed ered as a possible animal model of depression more activity in the peripheral area of the (Hartley, Neill, Hagler, Kors, & Vogel, 1990; open field test and a decrease in sexual activ- Neill, Vogel, Hagler, Kors, & Hennessey, ity of male rats (lower number of ejaculations 1990; Vogel, Neill, Hagler, & Kors, 1990a, and intromissions per mount). In addition, 1990b; Vogel, G. & Vogel, F., 1982). they demonstrated more sleep onset REM pe- A productive approach to advance the riods and more intermittent muscle twitches causal knowledge of psychopathology is to during REM sleep (Mirmiran et al., 1980, develop animal models which reproduce the 1981; Mirmiran, Scholtens, van de Poll, behavioral and neurophysiological aspects Uylings, van der Gusten, & de Boer, 1983). under controlled conditions so as to isolate the The American Psychiatric Association’s causal factors. It is obviously impossible to Diagnostic and Statistical Manual of Mental model all the dimensions of mental alterations, Disorders (DSM IV, 1994) specifies that some such as depression in humans in rats. The of the symptoms of Major Depressive Disor- purpose is to model some aspects of neuro - der are a sharp decline of interest in or psychological alterations that offer a con- capacity for pleasure, significant gain or loss vergent approach with the data provided by of weight, alterations in sleep (insomnia or clinical and descriptive studies. The aim of this hypersomnia), psychomotor acceleration or work was to analyze the principal research of retardation, recurrent thoughts of death or this area. suicide, feelings of guilt or uselessness, fatigue or loss of energy. Some of these symptoms can be studied using animal models, BEHAVIORAL ALTERATIONS while others clearly belong to the human area. From this perspective, different researchers REM SLEEP have documented the presence of some of these symptoms in adult CLI - treated rats. For As mentioned above, neonatal exposure of example, CLI - treated rats present sexual CLI results in alterations of REM sleep when abnormalities that could be considered sexual the animals reach adulthood. Experimental deficiencies, like a decrease in motivation and rats aging from 6 to 11 months, compared to sexual performance found in depression; the control groups, demonstrate continuous alter - increased locomotor activity found in the ations in REM sleep: higher percentage, lesser open field test could be similar to the motor latency of appearance, and increase in the

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frequency of the periods during sleep, and adrenergic availability, decreases REM sleep; abnormal temporary rebound course REM, Velázquez-Moctezuma, Aguilar-García, & in the presence of a total normal rebound Diaz-Ruiz, 1993). In adulthood, only those (Vogel, Neill, Kors, & Hagler, 1990). In animals treated with CLI showed greater contrast, no differences are found between periods of immobility in the forced swim test experimental subjects and the control group and a decrease in different sexual parameters; in sleep time, the number of times they no differences were found between subjects awake or in the average duration of the that had been treated with the other drugs. This periods they remain awake. result suggests that behavioral abnormalities The alterations in REM rhythm are those are not due to the deprivation of REM sleep of depression. For example, the decrease of that occurs during the neonatal period nor are REM latency is an indisputable marker of they related to the increased availability of unipolar depression. Because of this it is cate cholamines at a synaptic level. In the same one of the most studied in CLI animals. direction, deprivation of REM sleep in an The changes observed in CLI - treated early stage of life is not sufficient to induce animals could be the consequence of REM the symptoms of depression that were observ- sleep suppression during the neonatal period, ed. On the other hand, the increase in the by CLI administration (Mirmiran et al., 1981), availability of catecholamines at the synaptic or could be due to alterations in mono- level does not induce itself the same depres - aminergic systems (Frank & Heller, 1997). To sive syndrome. test these possibilities, neonatal rats were administered with three types of drugs which suppress REM sleep but with different actions IMMOBILITY IN FORCED SWIM TEST on the monoamine systems: CLI (a serotonin and noradrenaline reuptake inhibitor), zimel - Forced swim test is one of the most widely idine (ZMI, a selective serotonin reuptake used procedures to evaluate antidepressive inhibitor) and desipramine (DMI, a selective drugs. In this, the immobility of the animal is noradrenaline reuptake inhibitor). The results reduced by those drugs that have an anti- indicate that it is the serotonergic system depressive action and also by non-pharmaco - disorder in the neonatal stage that provokes logical antidepressive treatments, e.g., REM the effects of REM sleep alteration during sleep deprivation and electro-convulsive adulthood, since the same results are found shocks. Adult rats treated with CLI during with CLI and ZMI, without effects with DMI. postnatal days, compared with those that This data suggests that the cause of the received vehicle, demonstrated more time of observed deficit in adulthood depends mainly immobility (Bhagya, Srikumar, Raju, & on the alterations in serotoninergic trans- Shankaranarayana Rao, 2008; Bonilla-Jai me, mission, and not on the suppression of REM Retana-Márquez, Vázquez-Palacios, & Veláz- sleep, since all the treated groups had experi - quez-Moctezuma, 2003; Vázquez-Palacios, enced REM sleep deprivation in the neonatal Bonilla-Jaime, & Velázquez-Moctezuma, stage (Frank & Heller, 1997). 2005; Velázquez-Moctezuma & Diaz-Ruiz, Another hypothesis that was tested in this 1992). This effect can be found from the age model was whether other adulthood altera- of three months, reaching a maximum peak at tions, such as forced swim and dysfunctions 6-7 months. Then, a spontaneous decline in sexual behavior, are due to REM sleep begins from 11 months (Vogel et al., 1990a). alterations caused by CLI administration. For The alterations are produced when CLI is this, different drugs were admini stered to the administered for a minimum of six days in rats during the neonatal period: CLI, vehicle, specific periods; from 14 to 20 days of age is scopolamine (a drug which deprives the the last period in which this procedure animal of REM sleep by blocking colinergic produces abnormalities in adulthood (Feng, activity) and idazoxan (a drug which increases Ma, & Vogel, 2001).

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Also, Hilakivi, L. and Hilakivi, I. (1987) and one which monitored total spontaneous and Fernández-Pardal and Hilakivi (1989) motor activity called Digiscan, at different found that the neonatal administration with ages (Hartley et al., 1990). In the open field, desipramine (DMI, a selective noradrenaline the increase in activity in the peripheral area reuptake inhibitor) was involved to a sub- was replicated at 4 and 6 months of age. sequent lengthening in immobility in the swim However, in the other apparatus, the increase test, same results were found with zimelidine in activity occurred only at three months of (ZMI, a selective serotonin reuptake inhib- age (Maciag et al., 2006). itor). Together, these results suggest that the The administration of antidepressive treat - animals are not only hyperactive in an acute ments caused a reversal in the immobility in stressful situation like the open field test, but forced swim test observed in CLI rats. The also in a relatively normal situation where the effect of acute, subchronic and chronic treat - test is longer, and that the changes depend of ment of nicotine, fluoxetine, and the com- the phase of the day that the test began. bi nation of both administrations in these Two effective treatments for depression animals was studied (Vázquez-Palacios et al., were tested regarding locomotor activity in an 2005). The acute, subchronic (7 days) and open field test with CLI rats: the adminis - chronic (14 days) treatment with nicotine tration of imipramine or four days of REM reversed the immobility of CLI rats in forced sleep deprivation (Vogel et al., 1990a). The swim test, while the effect of fluoxetine was first treatment significantly reduced the only observed after its subchronic and chronic activity of CLI - treated animals. In contrast, administration. With the combination of REM sleep deprivation increased the activity nicotine and fluoxetine, no synergetic actions of CLI - treated animals. These preliminary were found. results indicate that treatment with imipramine normalizes the hyperactivity of CLI- LOCOMOTOR ACTIVITY treated animals found in this test, but with other treatments the alteration is accentuated. One of the behavioral changes initially observed in CLI - treated rats was the increase in activity during adulthood measured in the PLEASURE SEEKING BEHAVIOR open field test (Hartley et al., 1990; Hilakivi, L., Sinclair, & Hilakivi, I., 1984; Mirmiran et One of the most relevant symptoms of de- al., 1983). Gaztelu, Montes, Barrenechea, pression is the inability to experience pleasure Romero, and Saiz-Ruiz (1996) found that the (DSM IV, 1994). To evaluate this, different in- increase in activity depend on the dark/light dicators of non sexual pleasure seeking have phase in which the test starts. When the been used: intracraneal self-stimulation, with animals were tested in the light phase they one or several intensities of stimulus; the su- found increase in activity, but no changes were crose or saccharin consumption during 24 observed when the animals were tested in the hours; and the exploration of a novel object in dark phase. As this increase in activity was not an open field. Compared to controls, CLI- found in the central area of the apparatus, is treated rats presented less intracraneal self- possible that the animals were not exploring stimulation at 7 months of age, but not at 4 and the place, but perhaps were trying to escape of 5 months. No differences were found between the experimental area. The increase in activity treatments in consumption of different con- was age dependent, which could be inter- centrations of sucrose when the animals were preted as an inverted U-shaped curve; due to evaluated monthly from 3 to 11 months of age. the finding that activity has a peak at four However, in another experiment, at seven months. months, it was found that CLI - treated ani- The same rats treated with CLI or vehicle mals consumed less saccharin solution than were tested in two apparatus, the open field controls (Vogel et al., 1990a, 1990b).

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Neonatally CLI treated rats consume less mounts and ejaculations (de Boer, Mirmiran, of a 1% sucrose solution than controls in a van Haaren, Louwerse, & van de Poll, 1989; preference test that was performed during Feng et al., 2003; Maciag et al., 2006; two hours with animals deprived of food and Mirmiran et al., 1980, 1981, 1983). A decrease water for 18 hours, and that had received pre- in the ejaculations of male Syrian hamsters vious training of 48 hours of exposure to treated with the oral administration of CLI in water and a 1% sucrose solution (Bhagya et adulthood were also founded (Boscarino & al., 2008). Parfitt, 2002). In the same study, it was shown On the other hand, a procedure of consum- that the daily oral administration of CLI for matory Successive Negative Contrast (cSNC) two weeks to pregnant female Syrian hamsters in animals that had been neonatally treated provoked in adult male offspring, with respect with CLI was perfomed (Ruetti, Justel, & to non-treated controls, a greater number of Mustaca, 2008). In this experiment, the exper- penetrations before reaching the first ejacu- imental animals had access during ten daily lation. Sexual alterations were replicated in the trials of 5 minutes each to a reward of high Long-Evans strain (Neill et al., 1990). In magnitude (32% sucrose solution, pre-shift addition, it was shown that deficits were phase) and then suddenly downshifted to a reversed with imipramine administration and lower magnitude one (4% sucrose solution, REM sleep deprivation, both treatments used post-shift phase), while the control group had as antidepressants (Vogel, Neill, Kors, & always access to the less preferred solution. Hagler, 1990). With the unexpected incentive downshift, the No alterations were found in the activity of animals suppressed the consum matory behav- the Hypothalamic-Pituitary-Gonadal (HPG) ior compared to the control group. During axis and the level of testosterone was normal. downshift, the CLI group, like the vehicle For this reason, it was excluded that the sexual group, reacted with a decrease in the consum- dysfunction of these animals was due to matory behavior with respect to those animals physiological alterations relative to testoster - that always received the 4% solution, but the one, it would be interesting to further in- CLI - animals experienced a recovery of the vesti gate whether other hormones involved in negative contrast in the second day of down- the HPG axis are implicated or if this deficit is shift. In contrast, the animals neonatally in- more related to alterations in motivation or jected with vehicle recover ed after three days reinforcement systems (Bonilla-Jaime et al., of contrast. 2003). Finally, CLI - treated animals showed less Three different drugs were administered to exploration of a novel object in the open field evaluate the recovery of sexual performance in test at the age of 3 and 4 months, but these CLI - treated rats: yohimbine (a selective alpha- differences disappeared when they reached 5 2 blocker), 8-OH-DPAT (a selective agonist of and 6 months of age (Vogel et al., 1990a). 5HT1A) and oxotremorine (a selective agonist of muscarinic receptors; Bonilla-Jaime, Retana- Márquez, & Veláz quez-Moctezuma, 1998). SEXUAL BEHAVIOR The administration of oxotremorine and yohimbine induced a slight improvement, One of the negative effects of serotonin while 8-OH-DPAT restor ed sexual performance reuptake inhibitors, like CLI, is the abnormal - to normal levels in CLI - treated subjects. ities in sexual behavior as a decreased libido Lower intracraneal self-stimulation, lower and failures to reach orgasm or to ejaculate consumption of saccharin or sucrose, and (Hendrick, Gitlin, Altshuler, & Korenman, alterations in the sexual behavior support the 2000). idea that CLI-treated animals have a dimin - Male Wistar rats neonatally treated with ished capacity for pleasure and could have CLI also exhibited sexual deficiencies in damage the basic system of reinforcement or adulthood, expressed as a lower number of pleasure. Furthermore, some antidepressive

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treatments reverse alterations in sexual perfor - similar to the consumption of control rats. In mance. control animals, the application of nicotine Nevertheless, we must be cautious with had no effect on this parameter. this conclusion. The decrease in intracraneal Hilakivi, L. and Hilakivi, I. (1987) found self-stimulation was shown in a specific that rats neonatally treated with DMI show period of the development of the subjects; the an increase in immobility in the forced swim differences in the consummatory behavior of test, and this was shortened with alcohol- saccharin and sucrose were demonstrated in treatment, suggesting that alcohol had an two publications and also during a limited age antidepressant-like effect on these animals. period. Regarding the exploration of a novel These studies are promising to test the object, the differences also appear to be space relationship between alcoholism, depression, and temporal specific. In addition, the test was and its possible treatments. performed in an open field, where the animals had already shown differences in their stress related behavior (Hartley et al., 1990). On the AGONISTIC RESPONSE other hand, novelty seeking is considered to be associated with the control of impulses, and CLI - treated rats showed abnormalities in does not only relate to an aspect of re in - the agonistic response that could be reverted forcement seeking (Ballaz, Akil, & Watson, with treatment for depression. One of the first 2007; Zheng, Tan, Luo, Xu, Yang, & Sui, studies evaluated the antidepressants effect on 2004). Besides, the disruptions in sexual the fighting response induced by electric behavior were due to the consummatory shocks; in this case two animals were placed aspect of this behavior, the motivation phase together in a chamber and received electric was not evaluated yet. Nonetheless, the shocks (Vogel, Hartley, Neill, Hagler, & Kors, positive findings encourage the further eval- 1988). The rats were evaluated during two uation of this animal model. weeks and immediately before the beginning of treatment (baseline). It was found that CLI- treated animals were significantly less ag- VOLUNTARY CONSUMPTION OF ALCOHOL AND NICOTINE gre ss ive than control groups. Then, the ani - mals received two antidepressive treat ments: Clinical studies suggest that depression 4 days REM sleep deprivation, or the adminis- facilitates the alcohol abuse and that nicotine tration of imipramine. Both treatments caused improves depressive states. This allows treat - an increase in the fighting response of CLI ment with nicotine to reduce the alcohol treated animals in comparison to controls consumption in depressed subjects. It is a with out treatment. documented fact that nicotine provokes anti- The diminished aggressive response of CLI depressive effects (Salin-Pascual, de la Fuen- - treated rats was replicated (Martínez te, García, & Drucker-Colin, 1995; Salin- González et al., 2002). In this case, anti- Pascual & Drucker-Colin, 1998; Salin-Pas- depressive treatment with nicotine was appli - cual, Rosas, Jiménez-Genchi, Rivera-Meza, & ed. CLI - treated animals that received nicotine Delgado-Parra, 1996). With these ideas in presented higher levels of aggression similar mind Martínez-González, Próspero-García, to control animals. Mihailescu, and Drucker-Colin (2002) treat ed male rats with CLI during neonatal days and tested several behaviors with or without nico- LEARNING tine treatment when the animals reached the adulthood. Effectively, CLI-treated rats Depression in humans is associated with consumed more alcohol than controls. Nico- alterations in cognitive processes. Several tine treatment induced a decrease in alcohol clinical studies demonstrated that depressed consumption in CLI-treated rats, which was subjects have alterations in the hippocampus,

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which causes a deficit in memory and learn- One way of evaluating HPA axis function ing (McEwen & Sapolsky, 1995; Sapol sky, is using a dexametasone suppression test 2000). (DST). There is evidence indicating that To our knowledge, two studies tested the people with endogenous depression present cognitive capacity of CLI - treated rats. The abnormalities in REM sleep associated with first one studied the effects of REM sleep a non suppressive response to DST, and deprivation on the learning of passive avoid - higher basal levels of cortisol (Asnis et al., ance task in rats neonatally treated with CLI 1983; Willner, 1985). Therefore, a direct (Prathiba, Kumar, & Karanth, 2000). There relation would exist between abnormalities in were three groups: CLI-treated rats received a REM sleep, DST and depression. In this treatment of REM sleep deprivation in respect, it was studied if animals treated with adulthood during four consecutive days, a CLI CLI demonstrated a normal response to DST, treated control group (without REM sleep and whether this response was affected by deprivation) and a group injected with vehicle REM sleep deprivation (Prathiba, Kumar, & during neonatal days remained without Karanth, 1998). When the animals reached 3 treatment. The rats were later tested in a months of age, the authors evaluated cortico- passive avoidance task. The results show ed sterone levels before and after the admin- that neonatally - CLI treated animals without is tration of DST, and also later, REM sleeps REM sleep deprivation had an improvement deprivation during four consecutive days. It in the task, while the CLI rats with REM sleep was found that, before treatment, CLI - deprivation behaved as animals that received treated animals had significantly higher basal vehicle neonatal treatment. The authors show- levels of corticosterone in comparison to ed that rats neonatally treated with CLI control animals. After the administration of improved the retention in the passive avoid- DST in CLI - treated animals, there was a ance task; and the deprivation of REM sleep significant increase in corticosterone levels, reverse this improvement, which according to and a non suppressive response. On the other the authors indicates that these animals had an hand, REM sleep deprivation reduced increase in the sensitivity of cholinergic sys- corticosterone levels in CLI animals in tem. comparison to control animals that were not The second study evaluated the performance exposed to this. The animals that received of CLI - treated rats, saline controls and intact REM sleep deprivation did not differ from controls in an eight arms radial maze, which is controls in corticosterone levels. In this way, a more complicated learning and memory task neonatal treatment with CLI affected the (Bhagya et al., 2008). CLI - treated rats ability to suppress corticosterone levels after exhibited a profound deterioration in learning the administration of DST, and increased compared to controls. basal levels in experimental subjects. This finding constitutes the first evidence that neo - natal treatment with CLI induces deregulation of the HPA axis. PHYSIOLOGICAL ALTERATIONS At present, there is also data indicating the existence of a hypoactivation of the HPA axis NEUROENDOCRINAL ALTERATIONS that is not consistent with the validity of the model that is being shown. The neonatal In human depression, neuroendocrinal administration of CLI induced, in adult alterations are presented as the deregulation animals, a lower response of the HPA axis of the Hypothalamic-Pituitary-Adrenal axis under a stressful situation (Ogawa, Mikuni, (HPA - McEwen, 2000; Sapolsky, 2000). The Kuroda, Muneoka, Mori, & Takahashi, experimental results were ambiguous with 1994). Specifically, CLI-treated rats were respect to the function of this axis in CLI- exposed for seven days to physical restriction treated animals. during two hours and blood samples were

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taken in different periods of time: before the because CLI is an anorexigenic compound restraint in housing chambers, during, and (Hansen & Mikkelsen, 1988). However, no after exposure to the stressor. It was found studies have tested this hypothesis. that, compared to appropriate controls, that CLI - treated animals did not differ in corticosterone basal levels, but presented a lower NEUROPHYSIOLOGICAL ALTERATIONS increase in plasma levels of this hormone during exposure to the stressor, and returned Several lines of evidence suggest that a faster to basal levels after the stress ended. In reduction in central serotoninergic system accordance with these results, it was found activity is involved in the physiology of that the HPA axis was affected by neonatal depression. The compounds that block sero - treatment with CLI (Bonilla-Jaime et al., tonin reuptake are effective antidepress ants 2003; Feenstra, van Galen, Te Riele, Botter - (Hansen & Mikkelsen, 1988). Furthermore, blom, & Mirmiran, 1996). The corticosterone the different treatments commonly used as levels before and after copulation were antidepressants improve serotoninergic trans- measured. The cortico sterone basal level was mission (Vázquez-Palacios et al., 2005). In the same in CLI - treated animals and controls, connection to this, the hypothalamic concen- but after copulation, there was a lower tration of serotonin was 20% diminish ed increase in experimental subjects with respect when experimental animals were compared to controls. The conclusion of the study was to their controls at one year of age (Feenstra that the adrenal response normally provoked et al., 1996). A significant increase in the by sexual performance was significantly expression of “5HT transporter mRNA” in diminished in CLI - treated animals. the dorsal raphe nucleus (DRN) after the To summarize, while it is true that some administration of selective and non-selective experimental results found that CLI - treated reuptake inhi bitors of serotonin was founded rats have a higher basal level of cortico - (Hansen & Mikkelsen, 1988). Regarding sterone than controls, others found that not these results, the indicators of neuronal only do they differ in basal level, also during serotoning firing in the DRN was diminished the stress situation; circulating corticosterone in experimental animals compared to their increases less and returns more rapidly to controls, which is consistent with the basal levels than control groups. For this hypothesis that serotoninergic neuro- reason, we can conclude that if alterations in transmission is diminished in depression the HPA axis indeed exist in CLI - treated (Kinney, Vogel, & Feng, 1997; Yavari, Vogel, animals, it is still unclear in which way the & Neill, 1993). Furthermore, neonatal admin- deregulation is manifested. istration of CLI or citalopram induced changes in the serotoninergic system, which includes a reduction in the immunoreactivity BODYWEIGHT in the DRN of the limited enzyme of serotonin production (Maciag et al., 2006). Another symptom that is found in the DSM The authors argue that because the citalopram IV for depressive disorder is the increase or is a selective serotonin reuptake that shows decrease in subjects’ weight. There is evidence no affinity for other sites they can say that the of this type of alteration in neonatally CLI - changes in serotonergic transmission during treated animals. Different studies found that a critical period of devel opment of the experimental animals in adulthood have lower organism is the responsible for the changes, weight in comparison to control groups (de such as depression found in adult subjects. Boer et al., 1989; Hansen & Mikkelsen, 1988; On the other hand, it has been shown that Maciag et al., 2006; Mirmiran et al., 1983; nicotine is related to the serotoninergic system Yoo, Bunnell, Crabbe, Kalish, & Dishman, (Mihailescu, Palomero-Rivero, Meade- Huer- 2000). This weight difference could be ta, Maz-Flores, & Drucker-Colin, 1998; Seth,

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Cheeta, Tucci, & File, 2002). As demonstrat- ment). These results were obtained in male ed in another study, nicotine has anti de- rats of different strains and in hamsters, and at pres sive effects, which suggests that these different months, the majority of them at 3-4 effects could involve serotoninergic trans- months, and some of them after the sixth, this mission (Váquez-Palacios et al., 2005). could be because some changes were caused Several evidences indicate that in depres - with the decrement in the age of the animals, sion, there is an increase in colinergic activity. further research is needed to elucidate this There are antecedents in which neonatally issue (Boni lla-Jaime et al., 2003; Frank & CLI - treated animals present altered sensi - Heller, 1997; Hartley et al., 1990; Neill et al., tivity of colinergic receptors in adulthood 1990; Vogel, G. & Vogel, F., 1982; Vogel et (Prathiba et al., 2000). Based on these results, al., 1990a, 1990b). an experiment was performed to study the In the methodological level two experi- activity of a soluble form of acethyl cholines - ments showed that the oral administration of terase (ACHE) in the hippo campus of CLI - CLI provoked alterations in the sexual treated animals in comparison to controls performance of adult hamsters. Potentially it (Mavanji & Datta, 2002). In the frontal lobe, could be a valuable method that needs to be the opposite was found: CLI -treated animals evaluated in other behaviors and other rodents. showed significantly lower levels of AChE. If positive results were obtained then there There were no differences between treatments would be a decrease in the common problems when AChE levels were measured in the associated with handling and injections, brain stem, hypothalamus, and in the septum. reducing possible sources of stress caused by One previously mentioned study concern - the procedure per se and improving the animal ing sexual alterations and their reversal, quality of life (Boscarino & Parfitt, 2002). suggested that CLI - treated animals have On the other hand, only one experiment cholinergic and adrenergic systems altera- showed that prenatal administration caused an tions, specifically in the muscarinic receptors, alteration in sexual performance of the adult while the serotoninergic system seems to be hamster (Boscarino & Parfitt, 2002). This preserved at least when dealing with altera- result, although minor, deserves to be further tions found in sexual performance (Bonilla- considered and because of its clinical impl- Jaime et al., 2003). ications. Neuroendocrinal alterations analogous to those found in human depression were also DISCUSSION discovered in CLI - treated rats, although the data is contradictory. These include HPA axis The reviewed data, although including alterations; while some authors found hypo - some contradictory results, allows us to make activity others found hyperactivity (Asnis et the following conclusions. Adult animals al., 1983; Bonilla-Jaime et al., 2003; Feenstra exposed to CLI in neonatal days showed et al., 1996; Ogawa et al., 1994; Willner, alterations in REM sleep, lower weight, 1985). disruptions in locomotor activity, less intra - Other results support the hypothesis that craneal self-stimulation, lower saccharin and alterations found in CLI - treated animals are sucrose consumption, less suppression of the due to alterations in serotoninergic transmis- consummatory behavior, sexual alterations in sion during a critical period of development, males, higher alcohol consumption, disrup- such as the neonatal stage; more specifically, a tions in the agonistic response and in learning reduction in the hypothalamic concentration of compared to untreated animals. Several of serotonin, like a decrease in the neuronal firing these abnormalities could be reversed with in the dorsal raphe nucleus (Feenstra et al., those treatments that are effective for treating 1996; Frank & Heller, 1997; Kinney et al., depression in humans (antidepressive drugs, 1997; Yavari et al., 1993). An increase in nicotine and REM sleep deprivation treat- colinergic activity was also found (Bonilla-

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Jaime et al., 2003; Prathiba et al., 2000; Ve - ical and behavioral alterations of depression, lázquez-Moctezuma et al., 1993), although the the advantages are invaluable. In this sense, data in this field is not as vast as that found in neonatal treatment with CLI is very promis - relation to the neurotransmission of serotonin. ing. All of these results suggest that rats treated with CLI during neonatal days present alter - ations in adulthood analogous to human depression, but also the data indicates that is not REFERENCES yet a valid model. Further research is needed, and we have to be cautious with the Asnis, G.M., Halbreich, U., Sachar, E.J., conclusions because there is some evidence Swaminathan, R., Ostrow, L.C., Novacenko, suggesting that this is a promising model but H., Davis, M., Endicott, J. & Puig-Antich, J. other does not support its validity. (1983). Plasma cortisol secretion and REM As commonly occur with all animal period latency in adult endogenous depres- models in psychopathology, certain human characteristics cannot be evaluated; in this sion. American Journal of Psychiatry, 140, case, recurrent thoughts of death or suicidal 750-752. thoughts, emotionally depressed state, feelings Ballaz, S., Akil, H. & Watson, S. (2007). Pre - of uselessness. Furthermore, in this case, some vious experience affects subsequent anxiety- deficiencies appear in limited periods of time, like responses in rats bred for novelty others cannot always be replicated, and others seeking. Behavioral Neuroscience, 121(5), require crucial experiments to verify the 1113-1118. mechanism of alteration. Bhagya, V., Srikumar B.N., Raju, T.R., & Clinical investigations with humans are Shankaranarayana Rao, B.S. (2008). Neo- revealing, but had difficulty in identifying the natal clomipramine induced endogenous de- etiology of the disorders, since the majorities pression in rats is associated with learning are correlational studies with very little control impairment in adulthood. Behavior and Brain of variables (Papini, Wood, Daniel, & Norris, 2006). Animal models allow for greater Research, 187, 1890-1894. empirical control, a greater possibility of Bonilla-Jaime, H., Retana-Márquez, S. & Veláz- manipulation of behavioral, neuro physiol- quez-Moctezuma, J. (1998). Pharmacolog - ogical, genetic or psychological variables ical features of masculine sexual behavior in (Mustaca & Kamenetzky, 2006). Additionally, an animal model of depression. Pharma- these models lets us to consider psycho- cology, Biochemistry and Behavior, 60(1), pathologies as determined behavioral proc- 39-45. esses which mechanisms can be scientifically Bonilla-Jaime, H., Retana-Márquez, S., Váz- understood (Hunziker & Pérez-Acosta, 2001) quez-Palacios, G. & Velázquez-Moctezuma, and to study the brain mechanisms implicated J. (2003). Plasma levels of corticosterone in the pathogenesis and treatment of the and testosterone after sexual activity in male disorder that, for ethical reasons, are not rats treated neonatally with clomipramine. possible to study on human subjects. Research with mice and rats constitute a valuable Behavior & Pharmacology, 14(4), 357-362. instrument if is considered that humans as Boscarino, B. & Parfitt, D. (2002). Chronic oral well as rodents evolved from common administration of clomipramine decreases mammalian ancestors (Papini, 2003). On the sexual behavior in the male Syrian hamster other hand, animal models also present (Mesocricetus auratus). Physiology & Be - disadvantages like those discussed previously. hav ior, 75, 361-366. Therefore, if a model like the neonatal de Boer, S., Mirmiran, M., van Haaren, F., administration of CLI achieves the repro- Louwerse, A. & van de Poll, N. (1989). duction of some symptoms, neuro physiolog-

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Neurobehavioral teratogenic effects of clo- ications, mood and male fertility. Psycho - mi pramine and alpha-methyldopa. Neu rot ox- neuro endocrinology, 25(1), 37-51. icology and Teratology, 11, 77-84. Hilakivi, L., Sinclair, D. & Hilakivi, I. (1984). Feenstra, M., van Galen, H., Te Riele, P., Effects of neonatal treatment with clomi - Botterblom, M. & Mirmiran, M. (1996). De- pramine on adult ethanol related behavior in creased hypothalamic serotonin levels in the rat. Developmental Brain Research, 15, adult rats treated neonatally with clomi pra - 129-132. mine. Pharmacology, Biochemistry and Be- Hilakivi, L. & Hilakivi, I. (1987). Increased havior, 55(4), 647-652. adult behavioral “despair” in rats neonatally Feng, P., Ma, Y. & Vogel, G. (2001). The critical exponed to desipramine or zimeldine: An window of brain development from suscep- animal model of depression? Pharmacology, tive to insusceptive effects of clomipramine Biochemistry and Behavior, 28, 367-369. neonatal treatment on sexual behavior. Devel- Hunziker, L. & Pérez Acosta, A. (2001). Mo- opmental Brain Research, 129, 107-110. delos animales en psicopatología: ¿Una con- Feng, P., Guan, Z., Yang, X. & Fang, J. (2003). tribución o una ilusión? [Animal models in Impairments of ERK signal transduction in Psychopathology: A contribution or an illu- the brain in a rat model of depression in- sion?]. Avances en Psicología Clínica La- duced by neonatal exposure of clomi pra - tino americana, 19, 37-50. mine. Brain Research, 991, 195-205. Kinney, G., Vogel, G. & Feng, P. (1997). Fernández-Pardal, J. & Hilakivi, L. (1989). Decreased dorsal raphe nucleus neuronal ac- Effect of low alcohol dose on behavioral tivity in adult chloral hydrate anesthetized “despair” in rats neonatally treated with an- rats following neonatal clomipramine treat- tidepressant drugs. Alcohol, 6, 93-95. ment: implications for endogenous depres- Frank, M. & Heller, H. (1997). Neonatal treat- sion. Brain Research, 756, 68-75. ments with the serotonin uptake inhibitors Maciag, D., Simpson, K., Coppinger, D., Lu, Y., clomipramine and zimelidine, but not the no- Wang, Y., Lin, R. & Paul, I. (2006). Neonatal radrenaline uptake inhibitor desipramine, antidepressant exposure has lasting effects disrupt sleep patterns in adult rats. Brain on behavior and serotonin circuitry. Neuro- Research, 768, 287-293. psychopharmacology, 31, 47-57. Gaztelu, J., Montes, J., Barrenechea, C., Romero, Martínez-González, D., Próspero-García, O., M. & Saiz-Ruiz, J. (1996). Changes in circa- Mihailescu, S. & Drucker-Colın, R. (2002). dian rhythm of activity in depression depend Effects of nicotine on alcohol intake in a rat on dark / light phase of test start. European model of depression. Pharmacology, Bio - Neuropsychopharmacology, 6(3), 102-103. chemistry and Behavior, 72, 355-364. Hansen, H. & Mikkelsen, J. (1988). Long-term Mavanji, V. & Datta, S. (2002). Clomipramine effects on serotonin transporter mRNA ex- treatment in neonatal rats alters the brain pression of chronic neonatal exposure to a acetylcholinesterase activity in adulthood. serotonin reuptake inhibitor. European Jour- Neuroscience Letters, 330, 119-121. nal of Pharmacology, 352, 307-315. McEwen, B. (2000). The neurobiology of stress: Hartley, P., Neill, D., Hagler, M., Kors, D. & From serendipity to clinical relevance. Brain Vogel, G. (1990). Procedure- and age-depen- Research, 886, 172-189. dent hyperactivity in a new animal model of Mc Ewen, B. & Sapolsky, R. (1995). Stress and endogenous depression. Neuroscience and cognitive function. Current Opinion in Neu - Biobehavioral Reviews, 14, 69-72. robiology, 5, 205-216. Hendrick, V., Gitlin, M., Altshuler, L. & Mihailescu, S., Palomero-Rivero, M., Meade- Korenman, S. (2000). Antidepressant med- Huerta, P., Maz-Flores, A. & Drucker-Colin,

218 INTERDISCIPLINARIA, 2011, 28, 2, 207-220 2do. trabajo - JUSTEL (17 de nov.):Maquetaci n 1 03/01/2012 12:27 p.m. PÆgina 219

Neonatal treatment with clomipramine and depression

R. (1998). Effects of nicotine and mecamy- International Journal of Psychology and lamine on rat dorsal raphe neurons. European Psychological Therapy, 6, 189-213. Journal of Pharmacology, 360, 31-36. Prathiba, J., Kumar, K. & Karanth, K. (1998). Mirmiran, M., van de Poll, N., Corner, M., de Hiperactivity of HPA in neonatal CLI model Boer, G. & van Oyen, H. (1980). Lasting se- of depression. Journal of Neural Transmis- quelae of chronic treatment with clomipra - sion,105, 1335-1339. mine during early postnatal development in Prathiba, J., Kumar, K. & Karanth, K. (2000). the rat. IRCS Journal of Medicine Science, Effects of REM sleep deprivation on cholin- 8, 200-202. ergic receptor sensitivity and passive avoid- Mirmiran, M., van de Poll, N., Corner, M., van ance behavior in clomipramine model of Oyen, H. & Bour, H. (1981). Suppression of depression. Brain Research, 867, 243-245. active sleep by chronic treatment with Ruetti, E., Justel, N. & Mustaca, A. (2008). A clomipramine during early postnatal devel- new depression animal model: Neonatal opment: Effects on adult sleep and behavior treatment with clomipramine facilitates the in the rat. Brain Research, 204, 129-146. recuperation on frustration. Paper presented Mirmiran, M., Scholtens, J., van de Poll, N., at the 14th Biennal Meeting International So- Uylings, H., van der Gusten, J. & de Boer, cie ty for Comparative Psychology Argen - G. (1983). Effects of experimental suppres- tinean Scientific Society. Buenos Ai res, Ar- sion of active (REM) sleep during early de- gen tina. velopment upon adult brain and behavior in Salin-Pascual, R., de la Fuente, J., García, P. & the rat. Developmental Brain Research, 7, Drucker-Colin, R. (1995). Effects of transder- 277-286. mal nicotine on mood and sleep in nonsmok- Mustaca, A.E. & Kamenetzky, G. (2006). Alco- ing major depressed patients. Psychophar ma- holismo y ansiedad: Modelos animales [Al- col ogy, 121, 476-479. co hol ism and anxiety: Animal models]. Salin-Pascual, R., Rosas, M., Jiménez-Genchi, International Journal of Psychology and A., Rivera-Meza, B. & Delgado-Parra, V. Psychological Therapy, 6 (3), 99-120. (1996). Antidepressant effect of transdermal Neill, D., Vogel, G., Hagler, M., Kors, D. & nicotine patches in nonsmoking patients with Hennessey, A. (1990). Diminished Sexual major depression. Journal of Clinical Psy - activity in a new animal model of endoge- chi atry, 57, 387-389. nous depression. Neuroscience and Biobe - Salin-Pascual, R. & Drucker-Colin, R. (1998). A havioral Reviews, 14, 73-76. novel effect of nicotine on mood and sleep Ogawa, T., Mikuni, M., Kuroda, Y., Muneoka, in major depression. NeuroReport, 9, 57-60. K., Mori, K., & Takahashi, K. (1994). Effects Sapolsky, R. (2000). The possibility of neuro- of the altered serotoninergic signalling by toxicity in the hippocampus in major depres- neonatal treatment with 5, 7-dihydrohytrypt- sion: A primer on neuron death. Society of amine, ritanserin or clomipramine on the Biological Psychiatry, 48, 755-765. adrenocortical stress response and the gluco- Seth, P., Cheeta, S., Tucci, S. & File, S. (2002). corticoid receptor binding in the hippocam- Nicotinic-serotonergic interactions in brain pus in adult rats. Journal of Neural Trans- and behavior. Pharmacology, Biochemistry mission [GenSect], 96, 113-123. and Behavior, 71, 795-805. Papini, M. (2003). Comparative Psychology of Vázquez-Palacios, G., Bonilla-Jaime, H. & Ve- surprising nonreward. Brain, Behavior and lázquez-Moctezuma, J. (2005). Antide pres - Evolution, 62, 83-95. sant effects of nicotine and fluoxetine in an Papini, M., Wood, M., Daniel, A. & Norris, J. animal model of depression induced by (2006). Reward loss as psychological pain. neonatal treatment with clomipramine. Pro -

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gress in Neuro-Psychopharmacology & Bio - Vogel, G., Neill, D., Hagler, M. & Kors, D. logical Psychiatry, 29(1), 39-46. (1990b). Decreased intracranial self-stimu- Velázquez-Moctezuma, J. & Diaz-Ruiz, O. lation in a new animal model of endogenous (1992). Neonatal Treatment With Clomi - depression. Neuroscience and Biobehavioral pramine Increased Immobility in the Forced Reviews, 14, 65-68. Swim Test: An attribute of animal models of Vogel, G., Neill, D., Kors, D. & Hagler, M. depression. Pharmacology, Biochemistry and (1990). REM sleep abnormalities in a new Behavior, 42, 737-739. animal model of endogenous depression. Velázquez-Moctezuma, J., Aguilar-García, A. & Neuroscience and Biobehavioral Reviews, Diaz-Ruiz, O. (1993). Behavioral effects of 14, 77-83. neonatal treatment with clomipramine, sco- Willner, P. (1985). Depression: A psychobiolog- polamine, and idazoxan in male rats. Phar - ical synthesis. New York: Wiley. macology, Biochemistry and Behavior, 46, Yavari, P., Vogel, G. & Neill, D. (1993). De- 215-217. creased raphe unit activity in a rat model of Vogel, G. & Vogel, F. (1982). A new animal endogenous depression. Brain Research, model of endogenous depression. Sleep Re - 611, 31-36. search, 11:222a. Yoo, H., Bunnell, B., Crabbe, J., Kalish, L. & Vogel, G., Hartley, P., Neill, D., Hagler, M. & Dishman, R. (2000). Failure of neonatal Kors, D. (1988). Animal depression model clomipramine treatment to alter forced swim by neonatal clomipramine: Reduction of immobility: Chronic treadmill or activity- shock induced aggression. Pharmacology, wheel running and imipramine. Physiology Biochemistry and Behavior, 31, 103-106. & Behavior, 70, 407-11. Vogel, G., Neill, D., Hagler, M. & Kors, D. Zheng, X., Tan, B., Luo, X., Xu, W., Yang, X. & (1990a). A new animal model of endogenous Sui, N. (2004). Novelty-seeking behavior depression: A summary of present findings. and stress-induced locomotion in rats of ju- Neuroscience and Biobehavioral Reviews, venile period differentially related to mor- 14, 85-91. phine place conditioning in their adulthood. Behavioral Processes, 65, 15-23.

Laboratorio de Psicología Experimental y Aplicada (PSEA) Instituto de Investigaciones Médicas (IDIM) Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires (UBA) Ciudad Autónoma de Buenos Aires República Argentina

Fecha de recepción: 13 de enero de 2010 Fecha de aceptación: 9 de febrero de 2011

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