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Felipe Cortés-Salazar1, Josué Omar Suárez Ortíz1, Nancy Mónica Cendejas Trejo1, Juan Manuel Mancilla-Díaz1, Verónica Elsa López-Alonso1, Rodrigo Erick Escartín-Pérez1* 1Neurobiology of Eating Laboratory, Universidad Nacional Autónoma de México, FES Iztacala. Tlalnepantla, México Recibido, mayo 2/2014 Referencia: Cortés-Salazar, F., Suárez Ortíz, J.
Concepto de evaluación, mayo 12/2014 O., Cendejas Trejo, N. M., Mancilla-Díaz, J. M., Aceptado, junio 23/2014 López-Alonso, V. E. & Escartín-Pérez, R. E. (2014). Effects of CB1 cannabinoid receptor activation in the nucleus accumbens shell on feeding behavior. Acta Colombiana de Psicología, 17(2): pp. 61-68. Obesity and its related pathologies are well- known health hazards. Although obesity and overweight have multifactorial causes, overeating is common in both of these conditions. According to animal models, endocannabinoids and their receptors in the brain play a key role in the genesis and development of obesity. It has been proposed that the cannabinoid receptors CB1 (RCB1) expressed in the nucleus accumbens shell (NAC) are involved in the increase of the hedonic properties of food. To test this hypothesis, this study aimed to assess the effects of activating the NACs RCB1 on standard food intake during the light phase of the light-dark cycle. The effects of activating the RCB1 with CP 55,940 and WIN 55-212-2 (0.125, 0.25 and 0.5 nmol) in the NACS on feeding behavior and the behavioral satiety sequence of rats were assessed. It was found that both agonists increased food intake and delayed expression of satiety during the light phase. These results suggest that cannabinoid agonists encourage food intake when motivation is low and palatability is normal. Key words: Cannabinoids, food, nucleus accumbens shell, behavioral satiety sequence. La obesidad y sus patologías relacionadas son riesgos de salud muy conocidos. Aunque la obesidad y el sobrepeso tienen causas multifactoriales, la sobreingesta de alimento es frecuente en estas condiciones. De acuerdo con modelos animales, los endocanabinoides y sus receptores en el cerebro juegan un papel clave en la génesis y desarrollo de la obesidad. Se ha propuesto que los receptores a canabinoides CB1 (RCB1) expresados en el núcleo accumbens shell (NAcS) están involucrados en el incremento de las propiedades hedónicas del alimento. Para probar esta hipótesis, este estudio tuvo como objetivo evaluar los efectos de la activación de los RCB1 en el NAcS sobre la ingesta de alimento estándar durante la fase de luz del ciclo luz-oscuridad. Se evaluaron los efectos de la activación de los RCB1 con WIN 55-212-2 y CP 55,940 (0.125, 0.25, y 0.5 nmol) en el NAcS sobre la conducta alimentaria y la secuencia de saciedad conductual en ratas. Se encontró que ambos agonistas aumentaron la ingesta de alimento y demoraron la expresión de la saciedad durante la fase de luz. Lo anterior sugiere que los agonistas canabinoides estimulan el consumo de alimento cuando la motivación por el mismo es baja y la palatabilidad es normal. Palabras clave: Canabinoides, alimentación, núcleo accumbens shell, secuencia de saciedad conductual. * R. Erick Escartín-Pérez. Neurobiology of Eating Laboratory, UNAM FES Iztacala. 1 Av. de los Barrios, Los Reyes Iztacala, Tlalnepantla, México, 54090, México. Tel: + (52 55) 56231333 ext 39717. FAX: + (52 55) 5390 Acknowledgements. Funding for this study was provided by UNAM DGAPA grant IN224811 and IN224214 and FESI PAPCA 15. CORTÉS-SALAZAR, SUÁREZ ORTÍZ, CENDEJAS TREJO, MANCILLA-DÍAZ, LÓPEZ-ALONSO, ESCARTÍN-PÉREZ A obesidade e suas patologias relacionadas são riscos de saúde muito conhecidos. Ainda que a obesidade e o sobrepeso possuam causas multifatoriais, a sobre ingestão de alimento é frequente nestas condições. De acordo com modelos animais, os endocanabinóides e seus receptores no cérebro jogam um papel chave na gênese e desenvolvimento da obesidade. Foi proposto que os receptores a canabinóides CB1 (RCB1) expressos no núcleo accumbens shell (NAcS) estão envolvidos no aumento das propriedades hedônicas do alimento. Para testar esta hipótese, este estudo teve como objetivo avaliar os efeitos da ativação dos RCB1 nos NAcS sobre a ingestão de alimento padrão durante a fase de luz do ciclo luz-escuridão. Avaliaram-se os efeitos da ativação dos RCB1 com WIN 55-212-2 e CP 55,940 (0.125, 0.25, e 0.5 nmol) no NAcS sobre a conduta alimentar e a sequência de saciedade condutual em ratos. Encontrou-se que ambos agonistas aumentaram a ingestão de alimento e demoraram a expressão da saciedade durante a fase de luz. Isso sugere que os agonistas canabinóides estimulam o consumo de alimento quando a motivação pelo mesmo é baixa e a palatabilidade é normal. Palavras chave: Canabinóides, alimentação, núcleo accumbens shell, sequência de saciedade conductual. Obesity and its related pathologies are well-known health the effects of activation of CB1R in the NAcS on feeding threats. Despite obesity and overweight have multifactorial behavior using the behavioral satiety sequence (BSS) analy- causes, recurrent over-consumption of energy dense foods sis. It is hypothesized that acute activation of CB1R in the is frequently present in these conditions. Those diets are NAcS will stimulate feeding when a standard chow food commonly highly palatable and may activate the brain is offered during the light phase of the photoperiod, when reward circuit (Bassareo & Di Chiara, 1999; Mellis, et al., the basal food intake is naturally low and the hedonically 2007), promoting over-consumption when these foods are positive sensory properties of food may be stimulated by freely available (Perello, Chuang, Scott & Lutter, 2010) or cannabinoid agonists. with limited access schedules (Berner, Avena & Hoebel, 2008; Dimitriou, Rice & Corwin, 2000). The nucleus accumbens shell (NAcS) plays a key role in processing the rewarding properties of stimuli, and sev- eral neurochemical signaling pathways interact to regulate A total of 38 male Wistar rats (UNAM, FESI México) dopamine release in the NAcS and contribute to provide weighting 220-240 g at the beginning sessions were used. rewarding and/or hedonic properties to food (Gardner, Rats were housed in clear plastic cages with an inverted 2005). The endocannabinoid system has been implicated 12x12 h light and dark cycle with standard food (LabDiet® in reward-driven feeding (Matias, Cristino & Di Marzo, formulab diet #5008) and water ad libitum. All experimen- 2008), and interestingly cannabinoid receptor 1 (CB1R) KO tal procedures complied with the Official Mexican Norm mice are resistant to diet-induced obesity, indicating that (NOM-062-ZOO-1999), entitled Technical Specifications energy dense foods require endocannabinoid signaling to for the Production, Care, and Use of Laboratory Animals. generate obesity (Quarta, et al., 2010). The experimental evidence indicates that the acute activation of CB1R in the Instruments and materials NAcS by administration of anandamide (Soria-Gómez, et Drugs and treatments. CP 55 940 (non-selective CB1R al., 2007) or 2-AG (Kirkham, Williams, Fezza & Di Marzo, agonist) and WIN 55 212-2 (non-selective CB1R agonist) 2002) consistently stimulates chow intake. (Tocris Cookson Inc., Ellisville, MO, USA). Both drugs Previous results in our laboratory showed that activation were dissolved in DMSO, Tween-80 and 0.9 % saline of CB1R in the paraventricular nucleus of the hypothalamus solution (4:2:94 v/v/v). Different doses of drugs were prevented the natural satiety sequence by modulating homeo- administered intra-NAcS according to the experimental static mechanisms (Escartín-Pérez, et al., 2009); nevertheless design in a volume of 0.5 μl at 0.2 μl/min. Fresh solutions activation of cannabinoid receptors in the NAcS might also of drugs were prepared before the injections. stimulate feeding by a different mechanism, for instance Behavioral test (food intake and behavioral satiety stimulating the hedonically positive sensory properties of sequence). Consumption of standard chow (g) was as- food. Accordingly, the present study was aimed to evaluate sessed in two independent periods of 60 min each (hour 1,

food intake stimulated by cannabinoids hour 2), 10 and 70 min post injection. The analysis of the and they had a surgical recovery period of five days with BSS was conducted in both 60 min observation periods, food and water ad libitum. which were divided in 12 segments (5 min bins). The Design and recordings. After the surgical recovery duration (s) of each behavior was measured from the period, animals were randomly assigned to independent videotape recording to the following mutually exclusive groups that received vehicle or different intra-NAcS treat- categories: Intake (standard food), resting (inactivity with ments of WIN 55 212-2 (0.125, 0.25, 0.5 nmol) or CP 55 or without closed eyes, head of the rat was on the cage 940 (0.125, 0.25, 0.5 nmol) and behavioral recordings were floor), activity (any other behavior different to feeding, conducted. Immediately after central injections, animals resting, and grooming including locomotion, smelling, were placed into their home cages with pre-weighted stan- sniffing, etc), and grooming (self-cleaning of any part dard chow; behavior was video-recorded and subsequently of the body). Durations of each behavioral category are measured to obtain the BSS during two consecutive hours presented in terms of duration (±SEM) over 12 periods (two recordings of 60 min each, hour 1 and hour 2). At the (5-min bins) per hour, and served as the measure of the end of the observations, food containers were removed progression of BSS (Escartín-Pérez, et al., 2009). and ingestion of food was calculated (g). Animals were Histology. After the behavioral tests, rats were given individually housed with food and water ad libitum. All a lethal dose of sodium pentobarbital and were beheaded, behavioral observations were conducted during the light brains were removed and fixed in 10% formalin for two phase of the light/dark cycle. days. Brains were sectioned at 100 μm in the coronal Statistical analysis. Analyses of data from food intake plane, and then positions of the cannulas and injection measurements were performed by two-way ANOVAs (dose sites were verified. Brains in which drugs were not ad- x hour) to calculate significance of the differences by intra- ministered in the NAcS were excluded from the present NAcS injections. When appropriate, the Bonferroni's test report (Figure 1). was performed. The criterion for statistical significance was p < 0.05. Data were analyzed using GraphPad Prism Version 5.0. Data from standard food consumption measurements (g) and the BSS (s) are expressed as means (± SEM) and are organized in two independent sections: 1) Food intake, and 2) Behavioral satiety sequence (BSS) analyses. Effects of cannabinoid receptors activation in the NAcS on food intake Firstly, it was investigated if intra-NAcS activation of Figure 1. Schematic representation of injection sites (black circles, cannabinoid receptors with two different agonists produced left) in the NAcS. significant changes in chow consumption in a situation where the basal intake is low (light phase of photoperiod). Consistent with reports that found a stimulatory effect of Surgery. All animals were anaesthetized with ketamine activation of CB1R in the nucleus accumbens, intra-NAcS and xilasine (112.5 mg/kg and 22.5 mg/kg I.P.) and were injections of WIN 55 212-2 (all doses) significantly increased stereotaxically implanted (unilaterally) with guide cannulas standard chow intake (interaction dose x hour F for injection in the nucleus accumbens shell (coordinates factor dose F = 7.511; factor hour F = 25.81;p< 0.05) AP +1.52 mm and ML -0.7 mm relative to bregma, DV during the first hour of observation, and the effect persisted -6.0 mm relative to dura mater) according to Paxinos and during the second hour of the behavioral record when a Watson's Atlas (1998). After surgery, animals were dose of 0.25 nmol was administered (Figure 2). admin- istered with benzathine penicillin (300,000 UI/kg, I.M.) CORTÉS-SALAZAR, SUÁREZ ORTÍZ, CENDEJAS TREJO, MANCILLA-DÍAZ, LÓPEZ-ALONSO, ESCARTÍN-PÉREZ Effects of cannabinoid receptors activation in the NAcS on the behavioral satiety sequence In order to assess the behavioral profile associated to the stimulatory effect of intra-NAcS cannabinoid receptor activation on chow intake, the BSS in the same periods of time (hour 1 and hour 2) was analyzed. It was found that control animals began the test eating during the first periods, but subsequently the time spent eating decreased while the time of resting increased, showing the transition from eating to resting after the third period of the first hour of observation; activity and grooming remained low dur- ing the complete test (hour 1 and hour 2). As expected, in the second hour, control animals spent time resting during almost the complete 60-min record, reflecting satiety (Fig. 4. A, B). Animals treated with 0.125 and 0.25 nmol of WIN Figure 2. Effects of intra-NAcS injections of different doses of WIN 55 212-2 showed a delayed transition from eating to rest- 55 212-2 (WIN) on standard chow intake during two behavioral re- ing in the first hour of observation (6th and 7th periods, cords (hour 1 and hour 2). Data expressed in terms of means ± SEM. respectively), resting less time and with a higher level of *p<0.05, ***p<0.001 vs vehicle group (Vh); n= 4-6 per group. activity (specially the 0.125 nmol dose) than control rats. During the second hour of observation, animals treated with Independent groups of rats were administered with the the lower dose of WIN 55 212-2 (0.125 nmol) remained non-selective cannabinoid receptor agonist, CP 55 940, comparable to the control group; however, the 0.25 nmol at different doses. It was found that the activation of can- dose induced new meals and a higher level of activity, nabinoid receptors in the NAcS (all doses of CP 55940) preventing the increase of the resting time as observed increased significantly standard chow intake (interaction in control animals (Figure 4. C, D, and E, F). Finally, the = 6.045 p<0.01; factor dose F higher dose of WIN 55 212-2 did not alter the behavioral p<0.001; factor hour F = 54.66;p< 0.001) during the profile observed in the control group. Nevertheless, animals first hour. No statistically significant effect on the second in this group spent more time eating during the beginning period of observation was found (Figure 3). of the first hour (Figure 4. G, H). The behavioral profile produced by intra-NAcS injec- tions of CP 55 940 (0.125, 0.25 and 0.5 nmol) was also assessed and it was found that all doses consistently de- layed the transition from eating to resting during the first hour of observation (after the 6th, 7th and 9th periods, respectively), with a corresponding increase on the time of activity (Figure 5. C, E, G). During the second hour of observation, the higher doses of CP 55 940 (0.25 and 0.5 nmol) decreased the time spent resting (Figure 5. F, H), while the lower dose (0.125 nmol) remained similar to the control group (Figure 5. D). The present study was aimed to test the hypothesis that acute activation of CB1R in the NAcS stimulate standard Figure 3. Effects of intra-NAcS injections of different doses of CP chow intake during the light phase of the photoperiod in 55 940 (CP) on standard chow intake during 2 behavioral records rats maintained on ad libitum chow. It is shown here that (hour 1 and hour 2). Data expressed in terms of means ± SEM. both WIN 55 212-2 and CP 55 940 increase standard chow ***p<0.001 vs vehicle group; n= 4-6 per group. intake and delay the expression of the natural satiety se- quence. According to the behavioral analyses carried out, intra-NAcS administration of CB1R agonists stimulates food intake stimulated by cannabinoids Figure 4. Behavioral satiety sequence of groups injected with vehicle (A, B), or WIN 55 212-2 0.125 (C, D), 0.25 (E, F) and 0.5 (G, H) nmol. Values are presented as mean (error bars represent SEM) of duration of each behavioral category (intake, resting, activity and groo- ming) during the two hours of the behavioral test (hour 1, hour 2). The vertical line (solid) indicates the moment in which the transition between intake and resting occurred; the vertical line (dotted) indicates that the transition between intake and resting occu rred before the beginning of the second behavioral record, n= 4-6 per group. CORTÉS-SALAZAR, SUÁREZ ORTÍZ, CENDEJAS TREJO, MANCILLA-DÍAZ, LÓPEZ-ALONSO, ESCARTÍN-PÉREZ Figure 5. Behavioral satiety sequence of groups injected with vehicle (A, B), or CP 55 940 0.125 (C, D), 0.25 (E, F) and 0.5 (G, H) nmol. Values are presented as mean (error bars represent SEM) of duration of each behavioral category (intake, resting, activity and grooming) during the two hours of the behavioral test (hour 1, hour 2). The vertical line (solid) indicates the moment in which the transition between intake and resting occurred; the vertical line (dotted) indicates that the transition between intake and resting occurred before the beginning of the second behavioral record, n= 4-6 per group. food intake stimulated by cannabinoids feeding during the light phase of the photoperiod, when of food-induced behavioral alterations, such as food- the basal intake is naturally low, suggesting that canna- seeking. Supporting this notion, it was demonstrated that binoid agonists consistently stimulate food consumption the deletion of CB1R decreased operant behavior and the when motivation for food is low and palatability is regular motivation to obtain highly palatable food in CB1 KO (standard chow). mice (Guegan, et al., 2013). Furthermore, the findings that Different studies have explored the role of cannabi- CB1R KO rodents are resistant to diet-induced obesity noid receptors in the hypothalamus (Verty, McGregor & (Ravinet-Trillou, Delgorge, Menet, Arnone & Soubrié, Mallet, 2005; Jamshidy & Taylor, 2001), indicating that 2004), and that over-activity of the endocannabinoid system the stimulatory effect of cannabinoids is related to the promotes an obese phenotype (Maccarrone, et al., 2010), homeostatic modulation of food intake. Furthermore, be- in conjunction with the cannabinoid-induced increase of havioral experiments have shown that rimonabant bilaterally activity observed in this study, suggest a functional con- microinjected into the NAcS selectively decreased highly nection between the endocannabinoid system, ineffective palatable food intake in an operant task (Guegan, et al., inhibition of responses and obesity. Accordingly, chronic 2013). Our results confirm and extend the previous evidence exposure to cannabinoid agonists should be studied in that intra-accumbens administration of anandamide or 2-AG order to determine if the cannabinoid-induced increase of increase standard chow consumption (Soria-Gómez, et activity is related to the impulsivity observed in obesity al., 2007; Kirkham, et al., 2002) by a behavioral-specific (Nederkoorn, Braet, Van Eijs, Tanghe & Jansen, 2006). mechanism. Taking together these findings, it seems pos- In spite of the pharmacological lack of selectivity of sible that cannabinoid receptors modulate feeding behavior WIN 55-212-2 and CP 55,940 at CB1 and CB2 receptors, simultaneously by two independent processes; the first one, there is no knowledge of reports of CB2 expression in the homeostatic, characterized by affecting energy balance and NAcS. Only multifocal expression of CB2 immunoreactiv- motivational processes (hunger, appetite, satiety) (Cota, et ity has been reported in different areas of rodent brains at al., 2003; Escartín-Pérez, et al., 2009); and the second one, levels much lower than those of CB1 receptors (cerebellum, hedonic, increasing the rewarding properties of food and hippocampus, olfactory tubercle, cerebral cortex, thalamus, its hedonically positive sensory properties (Di Patrizio & amygdala, basal ganglia, periaqueductal gray) (Gong, et al., Simansky, 2008). 2006). Nevertheless, conclusive pharmacological evidence Despite the fact that the lower doses of WIN 55 of the CB1R participation in the reported effects should be 212-2 (0.125 and 0.5 nmol) and all doses of CP 55 940 provided (i.e. administering selective antagonists). increased the time of activity (especially in the first hour In summary, activation of CB1 receptors in the nucleus of observation), this effect did not disrupt the behavioral accumbens shell stimulates standard chow intake during the profile associated to post-ingestive satiety sequence ei- light phase of the photoperiod, when the basal food intake is ther the transition from eating to resting, suggesting that naturally low and the hedonically positive sensory properties the endocannabinoid system in this particular conditions of food may be stimulated. Further research should explore promotes feeding and increases motor activity. It is well in detail the relationship between the endocannabinoid know that cannabinoids affect motor behavior via CB1R system, impulsivity, and obesity. by regulating glutamatergic and GABAergic transmission (González, et al., 2009). Specifically, cannabinoid recep- tors located in basal ganglia modulate both the inhibi- tory and the excitatory neuronal transmission, providing Bassareo, V. & Di Chiara, G. (1999). Modulation of feeding- regulation of movement (Sanudo-Pena, Patrick, Patrick induced activation of mesolimbic dopamine transmission & Walker, 1996). Several reports showed that systemic by appetitive stimuli and its relation to motivational state. European Journal of Neuroscience, 11(12), 4389-4397. administration of the cannabinoid receptor agonist WIN 55,212-2 stimulated locomotor activity in the open field Berner, L. A., Avena, N. M. & Hoebel, B. G. (2008). Bingeing, self-restriction, and increased body weight in rats with li- test at low doses (0.25-0.6 mg/kg) (Pandolfo, Pamplona, mited access to a sweet-fat diet. Obesity (Silver Spring) Prediger & Takahashi, 2007; Drews, Schneider & Koch, 2005) and this effect was described as a general motor Cota, D., Marsicano, G., Tschöp, M., Grübler, Y., Flachskamm, stimulating effect. Nevertheless, in the present study both C., Schubert, M., Auer, D., Yassouridis, A., Thöne-Reine- cannabinoid agonists were administered intra-NAcS and ke, C., Ortmann, S., Tomassoni, F., Cervino, C., Nisoli, E., the behavioral profile elicited should not be considered Linthorst, A. C., Pasquali, R., Lutz, B., Stalla, G. K. & Pa- as a general stimulating effect, since the endogenous can- gotto, U. (2003). The endogenous cannabinoid system affects nabinoid system is strongly involved in the development CORTÉS-SALAZAR, SUÁREZ ORTÍZ, CENDEJAS TREJO, MANCILLA-DÍAZ, LÓPEZ-ALONSO, ESCARTÍN-PÉREZ energy balance via central orexigenic drive and peripheral li- Melis, T., Succu, S., Sanna, F., Boi, A., Argiolas, A. & Melis, pogenesis. Journal of Clinical Investigation, 112, 423-431. M. R. (2007). The cannabinoid antagonist SR 141716A Di Patrizio, N. V. & Simansky, K. J. (2008). Activating para- (Rimonabant) reduces the increase of extra-cellular dopa- brachial cannabinoid CB1 receptors selectively stimulates mine release in the rat nucleus accumbens induced by a feeding of palatable foods in rats. Journal of Neuroscience, novel high palatable food. Neuroscience Letters, 419 (3), 28(39),9702-9709. Dimitriou, S. G., Rice, H. B. & Corwin, R. L. (2000). Effects Nederkoorn, C., Braet, B., Van Eijs, Y., Tanghe, A. & Jansen, A. of limited access to a fat option on food intake and body (2006). 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UNDP Justice System Programme UNDP Justice System Programme Welcome to Timor- Leste Mai Ho Ksolok Iha Timor- Leste Partially compiled September 2003 UNDP Justice System Programme TABLE OF CONTENTS WELCOME TO TIMOR-LESTE.5 MAP OF TIMOR-LESTE.6 FACT SHEET ON TIMOR-LESTE.8 ADMINISTRATIVE DIVISION OF TIMOR-LESTE.9 BRIEF HISTORICAL OVERVIEW.10

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HERZIENING RICHTLIJN HOGE BLOEDDRUK KWALITEITSINSTITUUT VOOR DE GEZONDHEIDSZORG CBO In samenwerking met: • Institute for Medical Technology Assessment• Nederlandsche Internisten Vereeniging• Nederlandse Hartstichting• Nederlandse Vereniging voor Cardiologie• Nederlands Huisartsen Genootschap• Nederlands Hypertensie Genootschap• Vereniging voor Epidemiologie