RESUMEN
Endocannabinoids and their receptors not only contribute to the control of natural processes of appetite regulation and energy balance but also have an important role in the pathogenesis of obesity. CB1 receptors (CB1R) are expressed in several hypothalamic nuclei, including the paraventricular nucleus (PVN), where induce potent orexigenic responses. Activation of CB1R in the PVN induces hyperphagia by modulating directly or indirectly orexigenic and anorexigenic signals; however, interaction among these mediators has not been clearly defined. CB1R mRNA is expressed in serotonergic neurons that innervate the PVN, and activation of 5-HT receptors in the PVN constitutes an important satiety signal. Some GABAergic terminals are negatively influenced by 5-HT, suggesting that the hyperphagic effect of CB1R activation could involve changes in serotonergic and GABAergic signaling in the PVN. Accordingly, the present study was aimed to characterize the neurochemical mechanisms related to the hyperphagic effects induced by activation of CB1R in the PVN, studying in vitro and in vivo changes induced by direct activation these receptors. Here, we have found that the neurochemical mechanisms activated by stimulation of CB1 receptors in the PVN involve inhibition of 5-HT release, resulting in a decrease of serotonergic activity mediated by 5-HT1A and 5-HT1B receptors and inducing disinhibition of GABA release to stimulate food intake. In conclusion, these neurochemical changes in the PVN are determinant to the cannabinoid-induced stimulation of food intake. Our findings provide evidence of a functional connection among CB1R and serotonergic and GABAergic systems on the control of appetite regulation mediated by endocannabinoids.
Asunto(s)
Ingestión de Alimentos/fisiología , Núcleo Hipotalámico Paraventricular/metabolismo , Receptor Cannabinoide CB1/fisiología , Receptores de Serotonina 5-HT1/fisiología , Antagonistas de la Serotonina/farmacología , Serotonina/metabolismo , Ácido gamma-Aminobutírico/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Anfetaminas/administración & dosificación , Anfetaminas/farmacología , Animales , Ácidos Araquidónicos/farmacología , Ciproheptadina/administración & dosificación , Ciproheptadina/farmacología , Interacciones Farmacológicas , Masculino , Microinyecciones , Piperazinas/administración & dosificación , Piperazinas/farmacología , Piperidinas/administración & dosificación , Piperidinas/farmacología , Piperidonas/administración & dosificación , Piperidonas/farmacología , Pirazoles/administración & dosificación , Pirazoles/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Pirroles/administración & dosificación , Pirroles/farmacología , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Serotonina/administración & dosificación , Serotonina/farmacología , Antagonistas de la Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacología , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacología , Tritio/metabolismoRESUMEN
Obesity is a serious worldwide health problem, affecting 20-40% of the population in several countries. According to animal models, obesity is related to changes in the expression of proteins that control energy homeostasis and in neurotransmission associated to regulation of food intake. For example, it has been reported that diet-induced obesity produces overexpression of dopamine D4 receptor (D4R) mRNA in the ventromedial hypothalamic nucleus (VMH) of mice. Neurons in the VMH send dense glutamatergic projections to other hypothalamic regions as the paraventricular nucleus (PVN), where multiple signals are integrated to finely regulate energy homeostasis and food intake. Although it is well established that dopaminergic transmission in the hypothalamus plays a key role in modulating feeding, the specific mechanisms involved in the activation of D4R in the PVN and its modulatory action on glutamate release and feeding behavior have remained unexplored. To fill this gap, we characterize the behavioral and neurochemical role of D4R in the PVN. In behavioral experiments, we examined the effects of activation of dopamine D4 receptors in the PVN on food intake and on the behavioral satiety sequence in rats exposed to a food-restricted feeding program. In vitro experiments were conducted to study the effects of activation of dopamine D4 receptors on [(3)H]glutamate release and on plasma corticosterone in explants of the PVN. We found that activation of D4R in the PVN induced inhibition of glutamate release and stimulated food intake by inhibiting satiety. Furthermore, activation of D4R in the PVN decreased plasma levels of corticosterone, and this effect was reverted by NMDA. According to our findings, D4R in the PVN may be a target for the pharmacotherapy for obesity as well as eating disorder patients who show restrictive patterns and overweight.
Asunto(s)
Ácido Glutámico/metabolismo , Hiperfagia/fisiopatología , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores de Dopamina D4/metabolismo , Animales , Benzamidas/farmacología , Corticosterona/sangre , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Interacciones Farmacológicas , Ingestión de Alimentos/efectos de los fármacos , Ayuno , Agonistas de Receptores de GABA-A/farmacología , Ácido Glutámico/farmacología , Hiperfagia/inducido químicamente , Masculino , Muscimol/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Piperazinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Ratas , Ratas Wistar , Saciedad/efectos de los fármacos , Tritio/farmacocinéticaRESUMEN
It has been shown that endogenous and exogenous cannabinoids substantially increase feeding. Despite evidence for a role of endocannabinoids in mediating food ingestion, the mechanisms by which CB1 receptor agonists and antagonists have an effect on motivational processes (hunger, satiety) as well as on specific food preference are not entirely understood. The purpose of this study was to investigate the effects of systemic injection of the CB1 receptor agonist, ACEA, on protein, carbohydrates and fat intake as well as on the behavioural satiety sequence (BSS) in pre-satiated rats. Following a 120-min access to a three pure nutrient diet (protein, carbohydrates and fat) at dark onset, male Wistar rats were injected intraperitoneally with ACEA (0.1, 0.25, 0.5 and 1.0 mg/kg). Immediately after the injection, animals were placed into separate experimental cages with free access to food and a single 60-min period was video recorded to evaluate the BSS; protein, carbohydrates and fat intake (g) was measured at the same period of time. Intake of carbohydrates was significantly increased and this effect was prevented by the pre-treatment with AM 251. Analysis of BSS showed that administration of 0.5 mg/kg of ACEA reversed the satiation induced by food ingestion by increasing the time spent eating and decreasing the time resting without altering the overall activity. The present results suggest that the stimulation of food intake induced by activation of CB1 receptors involves a specific dietary component and behavioural selective mechanisms (stimulating hunger and inhibiting satiety).