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Cocaine not only increases brain dopamine levels but also activates the sigma 1 receptor (σ 1 R) that in turn regulates orexigenic receptor function. Identification of interactions involving dopamine D 1 (D 1 R), ghrelin (GHS-R 1a ), and σ 1 receptors have been addressed by biophysical techniques and a complementation approach using interfering peptides. The effect of cocaine on receptor functionality was assayed by measuring second messenger, cAMP and Ca 2+ , levels. The effect of acute or chronic cocaine administration on receptor complex expression was assayed by in situ proximity ligation assay. In silico procedures were used for molecular model building. σ 1 R KO mice were used for confirming involvement of this receptor. Upon identification of protomer interaction and receptor functionality, a unique structural model for the macromolecular complex formed by σ 1 R, D 1 R, and GHS-R 1a is proposed. The functionality of the complex, able to couple to both Gs and Gq proteins, is affected by cocaine binding to the σ 1 R, as confirmed using samples from σ 1 R -/- mice. The expression of the macromolecular complex was differentially affected upon acute and chronic cocaine administration to rats. The constructed 3D model is consistent with biochemical, biophysical, and available structural data. The σ 1 R, D 1 R, and GHS-R 1a complex constitutes a functional unit that is altered upon cocaine binding to the σ 1 R. Remarkably, the heteromer can simultaneously couple to two G proteins, thus allowing dopamine to signal via Ca 2+ and ghrelin via cAMP. The anorexic action of cocaine is mediated by such complex whose expression is higher after acute than after chronic administration regimens., (© 2021 Society for the Study of Addiction.)