title: Stimulation of dopamine D4 receptors in the paraventricular nucleus of the hypothalamus of male rats induces hyperphagia: involvement of glutamate.
abstract: 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.
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico.
authors.forename: Juan Gabriel
authors.initials: JG
authors.lastname: Tejas-Juárez
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico.
authors.forename: Ana María
authors.initials: AM
authors.lastname: Cruz-Martínez
authors.affiliation: Laboratory of Neurobiology of Eating, Universidad Nacional Autónoma de México, FES Iztacala, Mexico.
authors.forename: Verónica Elsa
authors.initials: VE
authors.lastname: López-Alonso
authors.affiliation: Department of Pharmacology, CINVESTAV-IPN, Mexico.
authors.forename: Brenda
authors.initials: B
authors.lastname: García-Iglesias
authors.affiliation: Laboratory of Neurobiology of Eating, Universidad Nacional Autónoma de México, FES Iztacala, Mexico.
authors.forename: Juan Manuel
authors.initials: JM
authors.lastname: Mancilla-Díaz
authors.affiliation: Department of Physiology, Biophysics & Neuroscience, CINVESTAV-IPN, Mexico.
authors.forename: Benjamín
authors.initials: B
authors.lastname: Florán-Garduño
authors.affiliation: Laboratory of Neurobiology of Eating, Universidad Nacional Autónoma de México, FES Iztacala, Mexico. Electronic address: escartin@campus.iztacala.unam.mx.
authors.forename: Rodrigo Erick
authors.initials: RE
authors.lastname: Escartín-Pérez
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects; D005215:Fasting; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006963:Hyperphagia / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D012527:Satiation / Q000187:drug effects; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D001549:Benzamides; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D058785:GABA-A Receptor Agonists; C477501:N-((4-(2-cyanophenyl)-1-piperazinyl)methyl)-3-methylbenzamide; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; C475158:RO 10-5824; D014316:Tritium; D050638:Receptors, Dopamine D4; D009118:Muscimol; D018698:Glutamic Acid; D003345:Corticosterone
keywords: Dopamine D4 receptor; Feeding; Glutamate; Paraventricular nucleus