Hypothalamic orexin, OX1, αMSH, NPY and MCRs expression in dopaminergic D2R knockout mice

García-Tornadú, Isabel; Dı́az-Torga, Graciela; Risso, Gabriela Sofía; Silveyra, Patricia; Cataldi, Natalia I.; Ramírez, María Cecilia; Low, Malcolm J.; Libertun, Carlos; Becú-Villalobos, Damasia

doi:10.1016/j.npep.2009.06.002

Cited by 24 publications

(24 citation statements)

References 61 publications

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“…There is other evidence, however, indicating that low basal levels of DA in mesocorticolimbic regions may also drive intake of these rewarding foods. Rats prone to overeating and becoming obese on a fat-rich diet exhibit reduced levels and evoked release of DA in both the NAc and mPFC (Geiger et al 2008; Rada et al 2010), and mice lacking the DA receptors D2 or D3, and hence having reduced DA function, consume more calories than WT mice with intact DA systems (Garcia-Tornadu et al 2009; Garcia-Tornadu et al 2010; McQuade et al 2004). Clinical studies also support the role of low DA in driving food intake, with antipsychotic medications that block dopaminergic activity causing patients to overeat and become obese (Blouin et al 2008; Kluge et al 2007).…”

Section: Neurochemicals Involved In Food and Macronutrient Intakementioning

confidence: 99%

Neurobiology of Consummatory Behavior: Mechanisms Underlying Overeating and Drug Use

Barson¹,

Morganstern²,

Leibowitz³

2012

ILAR Journal

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Consummatory behavior is driven not just by caloric need but also by emotional need. In the last several decades, a wide variety of models have been used to study the systems that drive food and drug intake. These include selective breeding for a specific trait, manipulation of gene expression, forced or voluntary exposure to a substance, and identification of biomarkers that predict which animals are prone to overconsuming specific substances. From this research, numerous brain areas and neurochemicals have been identified that drive consummatory behavior. While energy homeostasis is primarily mediated by the hypothalamus, reinforcement is more strongly mediated by nuclei outside of the hypothalamus, in mesocorticolimbic regions. Orexigenic neurochemicals that control food intake can provide a general signal for promoting caloric intake or a more specific signal for stimulating consumption of a particular macronutrient, fat, carbohydrate or protein. Those involved in controlling fat ingestion, including galanin, enkephalin, orexin, melanin-concentrating hormone and the endocannabinoids, show positive feedback with this macronutrient, with these peptides both increasing fat intake and being further stimulated by its intake. This positive relationship offers some explanation for why foods high in fat are so often overconsumed. Consumption of ethanol, a drug of abuse that also contains calories, is similarly driven by these neurochemical systems involved in fat intake, consistent with evidence closely relating fat and ethanol consumption. Further understanding of these systems involved in consummatory behavior will allow researchers to develop effective therapies for the treatment of overeating as well as drug abuse.

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Section: Neurochemicals Involved In Food and Macronutrient Intakementioning

confidence: 99%

Neurobiology of Consummatory Behavior: Mechanisms Underlying Overeating and Drug Use

Barson¹,

Morganstern²,

Leibowitz³

2012

ILAR Journal

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“…We found that in female and not in male mice, disruption of the D2R produced two potentially anorexigenic events: an increase in serum and hypothalamic α-MSH, and a decrease in hypothalamic orexin expression [53]. The very high chronic prolactin levels found in this sex probably counterbalance these effects.…”

Section: D2rs and Peptides Related To Food Intakementioning

confidence: 99%

“…In Drd2 –/– males, on the other hand, hypothalamic orexins and serum or hypothalamic α-MSH were not modified, and therefore the moderate hyperprolactinemia may account for increased food intake. These results suggest a sexually dimorphic participation of the D2R in food intake regulation [53], probably secondary to their regulation of prolactin secretion. A negative modulation of D2Rs on α-MSH release and a positive action on the hypothalamic expression of orexins is also suggested, which may function to maintain food intake at almost equilibrium.…”

Section: D2rs and Peptides Related To Food Intakementioning

confidence: 99%

New Insights into the Endocrine and Metabolic Roles of Dopamine D2 Receptors Gained from the <i>Drd2</i><sup>–/–</sup> Mouse

García-Tornadú

Millán²,

Recouvreux³

et al. 2010

Neuroendocrinology

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Dopamine D2 receptor (D2R) participation in prolactin regulation is well documented, but the role of D2Rs in the control of other hormones involved in growth, food intake and glucose metabolism has not been extensively studied. The study of D2R knockout mice (Drd2^–/–) puts forward new insights into the role of the D2R in growth hormone (GH)-releasing hormone-GH regulation, peptides involved in food intake, glucose homeostasis, as well as in prolactinoma development. The expected phenotype of chronic hyperprolactinemia and prolactinoma development was found in the Drd2^–/– mouse, and this model constitutes a valuable tool in the study of dopamine-resistant prolactinomas. Unexpectedly, these mice were growth retarded, and the importance of functional hypothalamic D2Rs in the neonatal period was revealed. In the Drd2^–/– mouse there was a failure of high neonatal GH levels and therefore the expansion of pituitary somatotropes was permanently altered. These mice also had increased food intake, and a sexually dimorphic participation of the D2R in food intake regulation is suggested. The effect described is probably secondary to D2R regulation of prolactin secretion. Furthermore, the negative modulation of D2Rs on α-melanocyte-stimulating hormone release and positive action on the hypothalamic expression of orexins reveals the complex D2R regulation of food intake. Finally, pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development in the Drd2^–/– mouse may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops. These results highlight the complex endocrine actions of the D2Rs at different levels, hypothalamus, pituitary or pancreas, which function to improve fitness, reproductive success and survival.

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“…Dopamine is released at the median eminence and conveyed by the hypothalamic portal system to regulate the activities of pituitary lactotrophs mainly via the type 2 dopamine receptor (D2R). Accordingly, D2R knockout mice display a phenotype characterized by chronic hyper-prolactinemia and the hyperplasia of lactotrophs (16,25). Although dopamine must exert its actions by binding to specific membrane receptors on pituitary endocrine cells, previous immunohistochemical studies of normal and tumoral lactotrophs have detected D2R immunoreactivities in the cytoplasm but not in the plasma membrane (18,41,48).…”

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confidence: 99%

Immunohistochemical demonstration of dopamine receptor D2R in the primary cilia of the mouse pituitary gland

2011

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Dopamine regulates the synthesis and secretion of prolactin and α-MSH/β-endorphin in lactotrophs and melanotrophs, respectively. While a predominant dopamine receptor, D2R, is known to be expressed in both the anterior and intermediate lobes of the pituitary gland, no previous immunohistochemical studies have shown the existence of D2R in the plasma membrane of pituitary endocrine cells. The present study clearly demonstrated a selective localization of the D2R immunoreactivity in primary cilia of lactotrophs and melanotrophs in the mouse adenohypophysis. Another immunoreactivity of D2R was found along the plasma membrane of melanotrophs. The intensity of immunoreactivity for D2R in the primary cilia of lactrotrophs changed during the estrous cycle and with genital conditions in contrast to a consistent immunolabeling in the melanotrophs. Since there is accumulating evidence that the primary cilium functions as a sensory device at a cellular level, the D2R-expressing primary cilia in the pituitary gland may be involved in the sensation of dopamine and dopaminergic compounds-though their involvement differs between the anterior and intermediate lobes.Dopamine is well established as a primary inhibitor of both prolactin secretion (6) and the proliferation of lactotrophs (1, 13). Dopamine is released at the median eminence and conveyed by the hypothalamic portal system to regulate the activities of pituitary lactotrophs mainly via the type 2 dopamine receptor (D2R). Accordingly, D2R knockout mice display a phenotype characterized by chronic hyper-prolactinemia and the hyperplasia of lactotrophs (16,25). Although dopamine must exert its actions by binding to specific membrane receptors on pituitary endocrine cells, previous immunohistochemical studies of normal and tumoral lactotrophs have detected D2R immunoreactivities in the cytoplasm but not in the plasma membrane (18,41,48). This is an inconsistent finding concerning the subcellular localization of D2R-though we sometimes experience such a discrepancy with the immunostaining of membrane-bound receptors. The pituitary intermediate lobe is also under the control of dopamine (10)(11)(12)17) and expresses D2R at a high density, unlike the anterior lobe (3). In situ hybridization analyses for D2R mRNA and radioligand binding assays in rats have demonstrated a condensed expression of D2R or dopamine binding sites in the intermediate lobe (28,32,35). The intermediate lobe morphologically differs from the anterior lobe by having rich innervation and poor vascularization (4, 26, 27) and being composed of essentially one type of endocrine cell, melanotrophs. The melanotrophs receive dopamine input from tuberohypophyseal neurons that actually terminate within the intermediate lobe (4). Dopamine has been experimentally shown to decrease the capacity of the intermediate lobe to synthesize pro-opiomelanocortin

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Hypothalamic orexin, OX1, αMSH, NPY and MCRs expression in dopaminergic D2R knockout mice

Cited by 24 publications

References 61 publications

Neurobiology of Consummatory Behavior: Mechanisms Underlying Overeating and Drug Use

Neurobiology of Consummatory Behavior: Mechanisms Underlying Overeating and Drug Use

New Insights into the Endocrine and Metabolic Roles of Dopamine D2 Receptors Gained from the <i>Drd2</i><sup>–/–</sup> Mouse

Immunohistochemical demonstration of dopamine receptor D2R in the primary cilia of the mouse pituitary gland

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