Cocaine Blocks Effects of Hunger Hormone, Ghrelin, Via Interaction with Neuronal Sigma-1 Receptors

David Aguinaga, Mireia Medrano, Arnau Cordomí, Mireia Jiménez-Rosés, Edgar Angelats, Mireia Casanovas, Ignacio Vega-Quiroga, Enric I. Canela, Milos Petrovic, Katia Gysling, Leonardo Pardo, Rafael Franco, Gemma Navarro

Research output: Contribution to journalArticleResearch

7 Citations (Scopus)

Abstract

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. 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 (σ 1 R) mediates cocaine anorectic effects by interacting in neurons with growth/hormone/secretagogue (ghrelin) receptors. Cocaine increases colocalization of σ 1 R 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 σ 1 R 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 σ 1 R-GHS-R1a complex, which arises as a key piece in the puzzle of the events linking cocaine consumption and appetitive/consummatory behaviors.
Original languageEnglish
Pages (from-to)1196-1210
JournalMolecular Neurobiology
Volume56
DOIs
Publication statusPublished - 1 Feb 2019

Keywords

  • Cross-regulation
  • Drug addiction
  • Functional selectivity
  • G protein-coupled heteroreceptor complex
  • Neuroendocrine
  • Receptor heteromer

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