Interdisciplinaria ISSN: 0325-8203 [email protected] Centro Interamericano de Investigaciones Psicológicas y Ciencias Afines Argentina 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 Available in: http://www.redalyc.org/articulo.oa?id=18022339003 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative 2do. trabajo - JUSTEL (17 de nov.):Maquetaci n 1 03/01/2012 12:27 p.m. PÆgina 207 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 INTERDISCIPLINARIA, 2011, 28, 2, 207-220 207 2do. trabajo - JUSTEL (17 de nov.):Maquetaci n 1 03/01/2012 12:27 p.m. PÆgina 208 Justel, Bentosela, Mustaca, and Ruetti 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 - treat ed 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 neuro transmission 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, neuro phy- reversed with those treatments that are sio logical 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 treat ment). 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 experi mental 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 208 INTERDISCIPLINARIA, 2011, 28, 2, 207-220 2do. trabajo - JUSTEL (17 de nov.):Maquetaci n 1 03/01/2012 12:27 p.m. PÆgina 209 Neonatal treatment with clomipramine and depression 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 (Mirmi ran, 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 specif ical - 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