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Cl- Agonists on Body Weight in Isolated Male Mice Psicothema, Vol Psicothema ISSN: 0214-9915 [email protected] Universidad de Oviedo España Martín López, Mercedes; Navarro, José Francisco Effects of gabaa/ώ/cl- agonists on body weight in isolated male mice Psicothema, vol. 10, núm. 1, 1998, pp. 167-173 Universidad de Oviedo Oviedo, España Disponible en: http://www.redalyc.org/articulo.oa?id=72710115 Cómo citar el artículo Número completo Sistema de Información Científica Más información del artículo Red de Revistas Científicas de América Latina, el Caribe, España y Portugal Página de la revista en redalyc.org Proyecto académico sin fines de lucro, desarrollado bajo la iniciativa de acceso abierto Psicothema, 1998. Vol. 10, nº 1, pp. 167-173 ISSN 0214 - 9915 CODEN PSOTEG ω EFFECTS OF GABAA/ /Cl- AGONISTS ON BODY WEIGHT IN ISOLATED MALE MICE Mercedes Martín-López and José Francisco Navarro Universidad de Málaga ω Numerous studies have demonstrated that GABAA/ /Cl- receptor agonists may increase body weight in grouped rodents. However, there is no evidence in relation to the possible actions of these drugs under isolation conditions. In this study, we examine the acute and subchronic effects of several doses of benzodiazepines (diazepam, clobazam, bentazepam and midazolam), cyclopyrrolones (zopiclone) and imidazopyridines (zolpi- dem) on body weight in isolated male mice. All animals were housed individually in transparent plastic cages during 30 days (non-drug period) and weighted weekly. After isolation period, drugs were administered acutely or daily for 10 consecutive days and body weights measured. Results showed that benzodiazepines, cyclopyrrolones and imi- dazopyridines did not vary significantly body weight, as compared with their saline groups. It is concluded that housing conditions can play a critical role in the modulation ω of GABAA/ /Cl- receptor agonists actions on body weight in mice. Numerosos estudios han demostrado que los agonistas del receptor ω GABAA/ /Cl- pueden incrementar el peso corporal en ratones agrupados. Sin embar- go, no existe evidencia respecto al efecto de dichos fármacos bajo condiciones de ais- lamiento. En el presente trabajo, examinamos el efecto de la administración aguda y subcrónica de varias dosis de benzodiazepinas (diacepam, clobazam, bentacepam y mi- dazolam), ciclopirrolonas (zopiclona) e imidazopiridinas (zolpidem) sobre el peso cor- poral en ratones machos aislados. Todos los animales fueron aislados en jaulas trans- parentes durante 30 días y pesados semanalmente. Tras el período de aislamiento, todos los fármacos fueron administrados aguda o subcrónicamente (10 días), registrándose los pesos de los animales. Los resultados mostraron que ninguno de los fármacos mo- dificó significativamente el peso corporal, en comparación con sus respectivos grupos controles. Se concluye que las condiciones de aislamiento pueden desempeñar un papel ω clave en la modulación de los efectos de los agonistas del receptor GABAA/ /Cl- so- bre el peso corporal en ratones. It is a well-documented fact that benzo- 1995). Presumably, the benzodiazepine-in- diazepines cause increased food consump- duced hyperphagia is mediated by actions at tion in many mammalian species (Cooper, central benzodiazepine (omega) recognition 1991; Nasure, 1994; Berridge and Peciña, sites, since it is reversed by the receptor an- tagonist flumazenil (Cooper et al, 1985). Correspondencia: José Francisco Navarro Moreover, it has been suggested that omega Área de Psicobiología receptors located in the parabrachial nu- Facultad de Psicología Campus de Teatinos. 29071 Málaga (Spain) cleus might be a site of action for the effects E-mail: [email protected] of benzodiazepines on ingestive behaviour 167 EFFECTS OF GABAA/ω/Cl- AGONISTS ON BODY WEIGHT IN ISOLATED MALE MICE (Higgs and Cooper, 1996). It has been pro- sed light schedule (lights on:20:00-08:00 posed that the benzodiazepine-induced incre- hrs), normal lab chow (Panlab, Barcelona, ase in food intake is due to an increase in the Spain) and tap water available “ad libitum”. palatability or hedonic value of food. Likewi- Mice were housed individually in transpa- se, partial agonists at omega receptors (such rent plastic cages (24 x 13.5 x 13 cm) during as bretazenil) can also enhance the ingestion 30 days (isolation period), being employed of food (Clifton and Cooper, 1996). On the as experimental or control animals. other hand, zopiclone (10 mg/kg) does not se- em to alter body weight in rats, although this Procedure action has been only observed in females. In contrast, zolpidem (that binds selecti- Non drug phase vely to ω1 receptor) does not affect food consumption. Therefore, there is not unrea- Animals, divided into four groups (ex- sonable to suggest that the hyperphagia ef- cept with diazepam) in each experiment (12 fect might be mediated by the type 2 recep- per group), were isolated for 30 days and tor (ω2) (Sanger and Zivkovic, 1988; Coo- changes in body weight were weekly mea- per, 1991). Barbiturates, which share many sured (at the same hour of the day and once of the pharmacological properties of benzo- a week) using a digital balance. diazepines, produce a strong stimulation of food intake, indicating that drug action at an Drug treatment phase ω alternative site in the GABAA/ /Cl- recep- tor complex can also lead to hyperphagia After 30 days without pharmacological (Cooper and Moores, 1985). treatment, mice were given intraperitoneally Although a considerable number of stu- acute or daily injections (during 10 days) of ω dies have demonstrated that GABAA/ /Cl- diazepam (0.5 and 2 mg/kg), clobazam receptor agonists may increase body weight, (0.75, 1.5 and 3 mg/kg), bentazepam (1, 3 all these investigations have been carried out and 5 mg/kg), midazolam (0.5, 1 and 1.5 using grouped animals, and there is no evi- mg/kg), zopiclone (1.5, 3 and 6 mg/kg) and dence in relation to the possible actions of zolpidem (0.75, 1.5 and 3 mg/kg), or phy- these drugs under isolation conditions. siological saline (0.9% NaCl) and were mo- The aim of this study was to examine the nitored daily for body weight. All drugs we- acute and subchronic effects of different re administered in a volumen of 10 ml/kg. ω GABAA/ /Cl- receptor agonists (benzodia- As statistical analysis, Mann-Whitney U- zepines, cyclopyrrolones and imidazopyridi- tests were used. nes) on body weight in isolated male mice. Results and Discussion Method Body weight did not vary significantly Animals between experimental and control groups during non-drug phase. 276 OF.1 strain albino male mice aged Figures 1 to 6, and table 1, illustrate the approximately 42 days (Servicio de Anima- evolution of mean body weight in all groups les de Laboratorio, Granada, Spain) in arri- during the drug treatment. As can be obser- ving to the laboratory were used. Mice we- ved, no significant differences between ex- re housed under standard laboratory condi- perimental and control groups were found tions: constant temperature (21 Cº), a rever- for the six drugs used. 168 Psicothema, 1998 MERCEDES MARTÍN-LÓPEZ AND JOSÉ FRANCISCO NAVARRO Benzodiazepines (diazepam, clobazam, that social isolation does not alter brain re- bentazepam, midazolam), cyclopyrrolones gional benzodiazepine binding site numbers (zopiclone) and imidazopyridines (zolpi- and affinity in rats (Morinan et al, 1992). dem) did not modify body weight of isola- Prolonged isolation can produce marked ted male mice after acute or subchronic tre- changes in brain neurotransmitter systems. atment, as compared with their control Thus, it has been reported that isolation pro- groups. These results indicate that stress vokes an increase of brain dopamine turno- produced by isolation appears to affect fee- ver, a slight decrease of brain noradrenaline ding responses and, consequently, to body turnover and a large decrease of brain sero- weight of animals. Therefore, housing con- tonin turnover (Valzelli, 1978). Moreover, a ditions (isolation or grouping) may influen- decrease of glutamic acid decarboxylase ac- ce differentially body weight of mice (Mar- tivity in the brain of isolated mice has also tín-López and Navarro, 1996). This action been reported (Blindermann et al, 1979), as has been previously described with other compared with grouped mice. More re- substances, such as morphine, which decre- cently, it has been demonstrated that social ased body weight in isolated mice but did isolation also can modify metabolic activity not affect to grouped mice (Espert et al, of the hippocampus, a limbic region in 1996). which GABAergic neurons are clearly pre- Although an appropriate interpretation of sent (Cimadevilla et al, 1997). isolation effects on body weight is unclear, In conclusion, housing conditions can it can be suggested that social isolation play an important role in the modulation of ω could lead pronounced changes in GA- GABAA/ /Cl- receptor agonists actions on ω BAA/ /Cl- receptor functions in the brain. body weight. Likewise, further studies are In fact, Early and Leonard (1977) have necessary in order to attempt to clarify the found lower levels of GABA in striatum, interactions between GABA and other hyppocampus and amigdala of isolated albi- brain neurotransmitters in the control of no mice in comparison with grouped mice. the effects of social isolation on body Nevertheless, others authors have found weight. Figure 1. Effects of diazepam on body weight in male mice. Psicothema, 1998 169 EFFECTS OF GABAA/ω/Cl- AGONISTS ON BODY WEIGHT IN ISOLATED MALE MICE Figure 2. Effects of clobazam on body weight in male mice. Figure 3. Effects of bentazepam on body weight in male mice. Figure 4. Effects of midazolam on body weight in male mice. 170 Psicothema, 1998 MERCEDES MARTÍN-LÓPEZ AND JOSÉ FRANCISCO NAVARRO Figure 5. Effects of zopiclone on body weight in male mice. Figure 6. Effects of zolpidem on body weight in male mice. References Berridge, K.C. and Peciña, S. (1995). Benzodia- (1997). Social isolation and energy metabo- zepines, appetite and taste palatability. Neu- lism in rat hippocampus.
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