RESUMO
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.
Assuntos
Ácido Glutâmico/metabolismo , Hiperfagia/fisiopatologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de Dopamina D4/metabolismo , Animais , Benzamidas/farmacologia , Corticosterona/sangue , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Interações Medicamentosas , Ingestão de Alimentos/efeitos dos fármacos , Jejum , Agonistas de Receptores de GABA-A/farmacologia , Ácido Glutâmico/farmacologia , Hiperfagia/induzido quimicamente , Masculino , Muscimol/farmacologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Ratos , Ratos Wistar , Saciação/efeitos dos fármacos , Trítio/farmacocinéticaRESUMO
Serotonin (5-HT) modulates the hypothalamic-pituitary-adrenal (HPA) axis response to stress. We examined the effect of chronic restraint stress (CRS; 20 min/day) as compared to control (CTRL) conditions for 14 days, on: 1) restraint-induced ACTH and corticosterone (CORT) secretion in rats pretreated with vehicle or SB-656104 (a 5-HT7 receptor antagonist); 2) 5-HT7 receptor-like immunoreactivity (5-HT7-LI) and protein in the hypothalamic paraventricular nucleus (PVN) and adrenal glands (AG); 3) baseline levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA), and 5-HIAA/5-HT ratio in PVN and AG; and 4) 5-HT-like immunoreactivity (5-HT-LI) in AG and tryptophan hydroxylase (TPH) protein in PVN and AG. On day 15, animals were subdivided into Treatment and No treatment groups. Treatment animals received an i.p. injection of vehicle or SB-656104; No Treatment animals received no injection. Sixty min later, Treatment animals were either decapitated with no further stress (0 min) or submitted to acute restraint (10, 30, 60 or 120 min); hormone serum levels were measured. No Treatment animals were employed for the rest of measurements. CRS decreased body weight gain and increased adrenal weight. In CTRL animals, acute restraint increased ACTH and CORT secretion in a time of restraint-dependent manner; both responses were inhibited by SB-656104. Exposure to CRS abolished ACTH but magnified CORT responses to restraint as compared to CTRL conditions; SB-656104 had no effect on ACTH levels but significantly inhibited sensitized CORT responses. In CTRL animals, 5-HT7-LI was detected in magnocellular and parvocellular subdivisions of PVN and sparsely in adrenal cortex. Exposure to CRS decreased 5-HT7-LI and protein in the PVN, but increased 5-HT7-LI in the adrenal cortex and protein in whole AG. Higher 5-HT and 5-HIAA levels were detected in PVN and AG from CRS animals but 5-HIAA/5-HT ratio increased in AG only. Finally, whereas 5-HT-LI was sparsely observed in the adrenal cortex of CTRL animals, it strongly increased in the adrenal cortex of CRS animals. No TPH protein was detected in AG from both animal groups. Results suggest that CRS promotes endocrine disruption involving decreased ACTH and sensitized CORT responses to acute restraint. This phenomenon may be associated with increased function and expression of 5-HT7 receptors as well as 5-HT turnover in AG.