PT - JOURNAL ARTICLE AU - Serge Guerreiro AU - Clelia Florence AU - Erwann Rousseau AU - Sabah Hamadat AU - Etienne C Hirsch AU - Patrick P Michel TI - The Sleep Modulating Peptide Orexin-B Protects Midbrain Dopamine Neurons from Degeneration, Alone or in Cooperation with Nicotine AID - 10.1124/mol.114.095703 DP - 2014 Dec 31 TA - Molecular Pharmacology PG - mol.114.095703 4099 - http://molpharm.aspetjournals.org/content/early/2014/12/31/mol.114.095703.short 4100 - http://molpharm.aspetjournals.org/content/early/2014/12/31/mol.114.095703.full AB - To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX) B provides partial but significant protection to spontaneously dying DA neurons whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport suggesting that they were functional. G-protein-coupled OX1 and OX2 receptors were both present on DA neurons but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype EMPA, suppressed this effect whereas a selective agonist [Ala11,D-Leu15]-OXB reproduced it. Survival promotion by OXB required intracellular calcium mobilization via IP3 and ryanodine receptors. Nicotine, a well-known neuroprotective molecule for DA neurons improved OXB-mediated rescue through the activation of α-bungarotoxin-sensitive (presumably α7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that is occurring in Parkinson disease might confer an increased vulnerability to midbrain DA neurons in this disorder.