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Cocaine blocks effects of hunger hormone, ghrelin, via interaction with neuronal sigma-1 receptors. Aguinaga Andrés, David Medrano Moya, Mireia Cordomí, Arnau Jiménez-Rosés, Mireia Angelats Canals, Edgar Casanovas Ferrero, Mireia Vega-Quiroga, Ignacio Canela Campos, Enric I. (Enric Isidre), 1949- Petrovic, Milos Gysling, Katia Pardo, Leonardo Franco Fernández, Rafael Navarro Brugal, Gemma Neuroendocrinologia Receptors cel·lulars Drogues Cocaïna Neuroendocrinology Cell receptors Drugs of abuse Cocaine Despite ancient knowledge on cocaine appetite-suppressant action, the molecular basis of such fact remains unknown. Addiction/eating disorders (e.g., binge eating, anorexia, bulimia) share a central control involving reward circuits. However, we here show that the sigma-1 receptor (σ1R) mediates cocaine anorectic effects by interacting in neurons with growth/hormone/secretagogue (ghrelin) receptors. Cocaine increases colocalization of σ1R and GHS-R1a at the cell surface. Moreover, in transfected HEK-293T and neuroblastoma SH-SY5Y cells, and in primary neuronal cultures, pretreatment with cocaine or a σ1R agonist inhibited ghrelin-mediated signaling, in a similar manner as the GHS-R1a antagonist YIL-781. Results were similar in G protein-dependent (cAMP accumulation and calcium release) and in partly dependent or independent (ERK1/2 phosphorylation and label-free) assays. We provide solid evidence for direct interaction between receptors and the functional consequences, as well as a reliable structural model of the macromolecular σ1R-GHS-R1a complex, which arises as a key piece in the puzzle of the events linking cocaine consumption and appetitive/consummatory behaviors. 2019-01-15T16:00:55Z 2019-06-07T05:10:09Z 2018-06-07 2019-01-15T16:00:55Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion Versió postprint del document publicat a: https://doi.org/10.1007/s12035-018-1140-7 Molecular Neurobiology, 2018, vol. 200, p. 1-10 https://doi.org/10.1007/s12035-018-1140-7 (c) Humana Press., 2018 info:eu-repo/semantics/openAccess Humana Press. Articles publicats en revistes (Bioquímica i Biomedicina Molecular)