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Redalyc.Timing of Progesterone and Allopregnanolone Effects in a Serial Salud Mental ISSN: 0185-3325 [email protected] Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz México Contreras, Carlos M.; Rodríguez-Landa, Juan Francisco; Bernal-Morales, Blandina; Gutiérrez-García, Ana G.; Saavedra, Margarita Timing of progesterone and allopregnanolone effects in a serial forced swim test Salud Mental, vol. 34, núm. 4, julio-agosto, 2011, pp. 309-314 Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz Distrito Federal, México Available in: http://www.redalyc.org/articulo.oa?id=58221317003 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 Salud Mental 2011;34:309-314Timing of progesterone and allopregnanolone effects in a serial forced swim test Timing of progesterone and allopregnanolone effects in a serial forced swim test Carlos M. Contreras,1,2 Juan Francisco Rodríguez-Landa,1 Blandina Bernal-Morales,1 Ana G. Gutiérrez-García,1,3 Margarita Saavedra1,4 Artículo original SUMMARY Total time in immobility was the highest and remained at similar levels only in the control group throughout the seven sessions of the The forced swim test (FST) is commonly employed to test the potency serial-FST. In the allopregnanolone group a reduction in immobility of drugs to reduce immobility as an indicator of anti-despair. Certainly, was observed beginning 0.5 h after injection and lasted approximately antidepressant drugs reduce the total time of immobility and enlarge 1.5 h. Similarly, progesterone reduced immobility beginning 1.0 h the latency to the first immobility period. FST is preceded by the open after injection, and the reduction lasted for approximately 5.0 h. In field test (OFT) to discard any influence of changes in general motor all groups, locomotion in the OFT was reduced after the first serial- activity that could interfere with immobility in the FST. Albeit FST session and remained at similar low levels during the serial-FST. progesterone and its α-reduced metabolite allopregnanolone produce In the control group, grooming was reduced after the first serial-FST antidepressant-like effects in the FST, the timing of actions is unknown. session and lasted 24 h, but grooming did not change in the We hypothesized that the latency and duration of effects produced by progesterone-or allopregnanolone-treated rats. progesterone and allopregnanolone may be characterized by From a serial-FST design, we conclude that progesterone and repeated FST sessions; we therefore devised a serial-FST experimental allopregnanolone exert short time-dependent reductions in immobility design to evaluate the timing effects of these steroids on immobility, and anti-stress-like effects no longer than 24 hrs, and seemingly a locomotion in the open field test, and grooming in the later as an reduction in the response to stress, which may have some clinical indicator of response to stress. applications. We included fifty-one ovariectomized adult Wistar rats weighing Key wordswords: Allopregnanolone, antidepressant, anti-stress, 200-250 g at the beginning of the experiments. They were grooming, progesterone, serial-forced swim test. ovariectomized by abdominal approach under anesthesia. Rats were housed six per cage, at room temperature (25 ± 1ºC) under a 12 h/12 h light/dark cycle (lights ON at 7:00 a.m.) with ad libitum access to RESUMEN purified water and food. All of the experimental procedures followed National Institutes of Health Guidelines. The local Ethics Committee Introducción (Biomedical Research Institute, Universidad Nacional Autónoma de La progesterona y su metabolito activo alopregnanolona se han estu- México) approved the experimental protocol. diado ampliamente en modelos experimentales de ansiedad y depre- A first group received vehicle (2-hidroxypropyl-γ-cyclodextrin sión, y por su propiedad de ser sintetizadas en el cerebro se les consi- dissolved in injectable sterilized water to obtain a 35% solution, control dera como neuroesteroides. Entre las pruebas que permiten determi- group n=17), the second group progesterone (1.0 mg/kg, n=17), and nar la potencia antidepresiva de ciertos fármacos se encuentra la prue- the third group allopregnanolone (1.0 mg/kg, n=17). All single injections ba de nado forzado, la cual se diseñó originalmente para detectar la were applied by intraperitoneal route at a volume of 0.8 ml/kg. potencia de sustancias con propiedades antidepresivas. Estas sustan- The effects of treatments were evaluated in the serial-FST at cias reducen el tiempo de inmovilidad y alargan la latencia al primer 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection, in a rectangular pool periodo de inmovilidad, lo cual es considerado como un efecto (height, 60 cm; length, 30 cm; width, 50 cm), with 24 cm deep water antidepresivo. Usualmente, la prueba de nado forzado se aplica dos (25 ± 1ºC). We evaluated the total time of immobility, during 5 min, veces, una sesión de preprueba que dura 15 minutos, en la cual la considered as the principal indicator of an anti-despair effect. Before rata o ratón desarrolla el estado de desesperanza. La preprueba es each session of serial-FST, locomotion was evaluated in the OFT seguida de la sesión de prueba que se realiza 24 horas después du- during 5 minutes. The apparatus consisted on an acrylic box (height, rante 5 minutos. En ella se evalúa el efecto de las sustancias con pro- 20 cm; length, 44 cm; width, 33 cm), with twelve squares delineated piedades antidepresivas. Además, la prueba de nado forzado es pre- on the floor (11 × 11 cm). In the same OFT sessions, grooming was cedida por la prueba de campo abierto con la finalidad de identificar evaluated as an indicator of response to stress. Statistical analysis cambios en la actividad motora general (hipoactividad o consisted in two-way analysis of variance (ANOVA) and Student- hiperactividad) que pudiera interferir con la interpretación de las va- Newman-Keuls as post hoc test. riables evaluadas en la prueba de nado forzado. 1 Laboratorio de Neurofarmacología, Instituto de Neuroetología, Universidad Veracruzana, Xalapa, Veracruz, México. 2 Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Xalapa, Veracruz, México. 3 Facultad de Psicología, Universidad Veracruzana, Xalapa, Veracruz, México. 4 Facultad de Química Farmacéutica Biológica, Universidad Veracruzana, Xalapa, Veracruz, México. Corresponding Author: Carlos M. Contreras. E.mail: [email protected] Recibido: 20 de mayo de 2011. Aceptado: 4 de julio de 2011. Vol. 34, No. 4, julio-agosto 2011 309 Contreras et al. Algunos esteroides, como la progesterona y alopregnanolona, a la rata en una caja de acrílico (base 33 × 44 cm, altura 20 cm) con reducen la inmovilidad y alargan la latencia a la primera inmovilidad el piso dividido en 12 cuadros de 11 × 11 cm. Los resultados obtenidos en la prueba de nado forzado, lo que indica su efecto tipo-antidepre- de ambas pruebas fueron evaluados por medio de una ANOVA de sivo. Sin embargo, la latencia y la duración de los efectos farmaco- dos vías y como prueba post hoc se aplicó Student-Newman-Keuls. lógicos son desconocidas. La hipótesis de este trabajo fue que, si utilizá- bamos la prueba de nado forzado de forma repetida, podríamos Resultados identificar el tiempo de duración de los efectos de estos esteroides. La prueba de nado forzado aplicada de forma repetida resultó ser Por lo tanto, diseñamos un experimento con la prueba de nado forzado útil para evaluar los efectos temporales producidos por dos esteroides seriada para evaluar el tiempo de permanencia de los efectos de con potencia antidepresiva. Las ratas del grupo control mostraron progesterona y alopregnanolona en esta prueba conductual. los valores más altos de inmovilidad en la prueba de nado forzado, los cuales se mantuvieron así durante las sesiones de prueba. En los Materiales y métodos grupos tratados con progesterona o alopregnanolona hubo una re- Sujetos: En este estudio se incluyeron 51 ratas adultas ovariectomizadas ducción de la inmovilidad, gradual y temporal. Los animales trata- de la cepa Wistar, con peso entre 200 y 250 g al inicio de los experi- dos con alopregnanolona redujeron la inmovilidad a partir de las mentos. Las ratas fueron anestesiadas y ovariectomizadas por aproxi- 0.5 horas después de la administración, efecto que se mantuvo por mación ventral y fueron alojadas en cajas de acrílico trasparente (n=6), un periodo de 1.5 h. Los animales tratados con progesterona redu- con una temperatura ambiente de 25 ± 1ºC y con un ciclo de luz- jeron la inmovilidad a partir de 1.0 hora después de la administra- oscuridad de 12 ×12 h (la luz se encendió a las 7:00 am). Las ratas ción, efecto que se mantuvo por un periodo de 5.0h. En campo abier- tuvieron libre acceso al agua purificada y al alimento (Purina). Todos to, independientemente del tratamiento, hubo una reducción del los procedimientos realizados en este estudio fueron de acuerdo con número de cuadros cruzados después de la primera sesión de nado las normas éticas en el uso de animales de experimentación, basán- forzado, efecto que permaneció hasta las 24h. En el acicalamiento, donos en la Guía del National Institute of Health, y el protocolo fue se observó que sólo los animales del grupo control redujeron aprobado por el Comité de Ética del Instituto de Investigaciones significativamente el tiempo empleado en esta conducta, mientras Biomédicas de la Universidad Nacional Autónoma de México. que los animales inyectados con progesterona o alopregnanolona Grupos y tratamientos: Las ratas del grupo control recibieron no modificaron esta variable. Es decir, mantuvieron niveles seme- el vehículo (solución al 35% de 2-hidroxipropil-g-ciclodextrina), el jantes durante todas las sesiones de prueba y estuvieron por arriba segundo grupo recibió progesterona (1.0 mg/kg) y el tercero recibió de los valores encontrados en los animales control.
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