Dopamine depresses melanin concentrating hormone neuronal activity through multiple effects on α2-noradrenergic, D1 and D2-like dopaminergic receptors.
Two neuronal populations of the lateral hypothalamus that, respectively, produce melanin-concentrating hormone (MCH) and orexin peptides are crucially involved in control of metabolism, feeding and related goal-oriented behaviors. In contrast to orexin neurons, mainly involved in short-term regulation of feeding, MCH neurons participate in long-term control of energy storage and body weight. Beyond its effect on feeding, MCH has also been shown to be involved in regulation of seeking behavior and addiction through modulation of dopamine (DA) metabolism. This regulation is essential for reinforcement-associated behaviors. Moreover, drugs of abuse, which increase extracellular DA levels, are known to decrease food intake. Consistent with this observation, DA has been shown to modulate orexin neurons of the lateral hypothalamus. However, no study is available concerning the effects of DA on MCH neurons. Whole-cell patch-clamp recordings were done in hypothalamic mouse brain slices. MCH neurons were identified by Tau-Cyan-GFP labeling using a transgenic mouse model (MCH-GFP). First, we show that DA (10-200 μM) induces an outward current in MCH neurons. However, this current is not due to activation of DA receptors, but mediated through activation of α2-noradrenergic receptors and subsequent opening of G-protein activated inward rectifier K+ (GIRK) channels. Current-clamp experiments revealed that this GIRK-activation leads to hyperpolarization, thus decreasing excitability of MCH neurons. Furthermore, we confirm that MCH neurons receive mainly GABAergic inputs rather than glutamatergic ones. We show that DA modulates these inputs in a complex manner: at low concentrations, DA activates D1-like receptors, promoting presynaptic activity, whereas, at higher concentrations (100 μM), D2-like receptor activation inhibits presynaptic activity. Overall, DA should lead to a decrease in MCH neuron excitability, likely resulting in down-regulation of MCH release and feeding behavior.
Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097, Centre National de la Recherche Scientifique (CNRS), 660 route des Lucioles, Valbonne, France.
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Conductier
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Nahon
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Guyon
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D007028:Hypothalamic Hormones / Q000235:genetics / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D018341:Receptors, Adrenergic, alpha-2; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C019463:melanin-concentrating hormone; D004298:Dopamine