63 4 Journal of Molecular D Aguinaga et al. Cocaine, ghrelin, sigma-1 63:4 R81–R92 Endocrinology receptors, and appetite REVIEW The sigma-1 receptor as key common factor in cocaine and food-seeking behaviors David Aguinaga1,2, Mireia Casanovas1,2, Rafael Rivas-Santisteban1,2, Irene Reyes-Resina1,2,†, Gemma Navarro2,3 and Rafael Franco1,2 1Department of Biochemistry and Molecular Biomedicine, School of Biology, Universitat de Barcelona, Barcelona, Spain 2Centro de Investigación en Red, Enfermedades Neurodegenerativas, CiberNed, Instituto de Salud Carlos III, Madrid, Spain 3Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain Correspondence should be addressed to R Franco or G Navarro: [email protected] or [email protected] †(I Reyes-Resina is now at Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany) Abstract Addiction and eating disorders involve brain reward circuits. Binge eating predisposes Key Words to addictive behavior, while the cessation of exposure to drugs of abuse leads to reward f Dopamine receptors activities, including intake of tasty foods. Cocaine use is associated with a decrease in f Ghrelin receptors food intake, with reversal after drug use is discontinued. Exciting new findings show that f Orexin receptors receptors for the ‘hunger’ hormone, ghrelin, directly interact with the sigma-1 receptor f MAP kinase (σ1R), which is a target of cocaine. σ1Rs are key players in regulating dopaminergic f Receptor heteromers neurotransmission and ghrelin-mediated actions. This review focuses on the σ1 receptor f Drug addiction as a general neuroendocrine regulator by directly interacting with neuronal G-protein- f Reward circuits of the CNS coupled receptors. This review also covers the early mechanisms by which cocaine f Calcium signaling binding to σ1 blocks the food-seeking behavior triggered by ghrelin. Those findings appear f cAMP/PKA signaling as fundamental to understand common mechanisms in drug addiction and eating disorders. Journal of Molecular Endocrinology (2019) 63, R81–R92 Introduction Food-seeking behavior involve peripheral and central a long history of use without fully understanding the players, ghrelin being one of the most relevant. Ghrelin mechanisms of action. Recent results show that one is synthesized in the stomach but its endocrine action atypical receptor of unknown physiological function, is exerted, among others, in heart, gastrointestinal (GI) the sigma-1 receptor (σ1R), is a key piece of the puzzle tract, pancreas and central nervous system (CNS) (Fig. showing interrelationships between cocaine and food- 1). Ghrelin, the ‘hunger’ hormone, acts via a specific seeking behaviors. First, this review covers the role of receptor, GHS-R1a, which belongs to the superfamily of σ1R in cocaine addiction via GPCR-mediated regulation G-protein-coupled receptors (GPCRs). Dopamine, one of of dopaminergic transmission. The second part covers the main neurotransmitters in the brain, is a key player recent data showing how sigma receptors regulate in the circuits in which neuronal GHS-R1a expression ghrelinergic signaling. Finally, the review presents the occurs. Also, dopamine is central to the actions of novel and relevant evidence linking cocaine-mediated a variety of drugs of abuse, in particular cocaine. suppression of appetite with both cocaine binding to South American tribes used cocaine for endurance σ1R and subsequent regulation of the functionality of enhancement and appetite suppression, indicating dopamine and ghrelin GPCRs. https://jme.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JME-19-0138 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/03/2021 01:56:11AM via free access -19-0138 Journal of Molecular D Aguinaga et al. Cocaine, ghrelin, sigma-1 63:4 R82 Endocrinology receptors, and appetite with synthetic drugs acting on σ2 receptors decreases some of cocaine-induced effects (Matsumoto et al. 2007) and that antagonist of the receptor counteract induced locomotor stimulation in cocaine-administered mice (Lever et al. 2014). However, the research on σ2 receptor is still too preliminary to allow establishing a solid link between the receptor and addiction mechanisms. One of the novel aspects in the review, which is based on recent results, is the advance in understanding how cocaine consumption reduces food-seeking behavior. Apparently, this is due to direct interactions with the receptor for the Figure 1 hunger hormone, ghrelin. Endocrine actions of ghrelin in different body organs. Ghrelin is produced in the stomach (yellow) and exerts actions in different parts of the The most striking and accepted effect of cocaine mammalian body. Examples of organs and actions are in green circles. in brain is an increase in inter- and extra-synaptic dopamine concentration that leads to marked activation Apart from acting via inhibition of dopamine of dopamine receptors (Fig. 2). These and many other transporters in neurons, cocaine is able to interact with neuronal receptors belonging to the family of GPCRs sigma-1 and sigma-2 receptors. The physiological role of the use cAMP as second messenger. Information taken from two receptors is unknown and, also, they are structurally the British Society guide for pharmacology shows sigma unrelated despite sharing the same name (sigma). This receptors’ atypical properties: they do not use either review focuses on σ1R as a mediator of the anorexigenic cAMP or any other second messenger as calcium ions effect of cocaine. The receptor, whose function remains a or inositol-3-phosphate. As σ1R are not coupled to any mystery, displays interesting features such as its capacity to known signal transduction machinery, the guide indicates (i) bind cocaine at physiologically relevant concentrations that ‘there is only a modest pharmacological overlap and and (ii) modulate GPCR function. Early evidence indicated no structural convergence with the GPCRs’ (http://www. a blockade of stimulant effect of cocaine by targeting σ1R guidetopharmacology.org/GRAC/FamilyDisplayForward? (Menkel et al. 1991). It should be noted that treatment familyId=785). On the other hand, structurally different Figure 2 Schema of σ1 receptor-mediated actions related with food intake and mediated by neuronal GPCRs. Cocaine increases extraneuronal dopamine concentration and activates σ1 receptors. Interactions of σ1 and dopamine receptors or dopamine receptor-containing heteromers indirectly regulate food-seeking behavior. Interactions with ghrelin, orexin or CRF receptors directly regulate food consumption habits. Arrows originating at σ1 receptors indicate proven (continuous ‘yes’) or suspected/unproven interactions. Dopamine receptors types appear as D1R, D2R, or D3R. Adenosine A2A receptors appear as A2AR. Histamine H3 receptors appear as H3R. Other abbreviations are for ghrelin (GHS-R1a), CRF (CRF1) and orexin (OX1) receptors. https://jme.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/JME-19-0138 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/03/2021 01:56:11AM via free access Journal of Molecular D Aguinaga et al. Cocaine, ghrelin, sigma-1 63:4 R83 Endocrinology receptors, and appetite compounds may bind to σ1R receptors at topologically haloperidol and (+)-pentazocine have opposite effects, intracellular sites. In fact, the binding of a drug seemingly thus paving the way to effectively test or select molecules acting on opioid receptors suggested that σ1R receptors with ‘agonistic’ versus opposite (‘antagonistic’) actions. belonged to the opioid receptor family. The uniqueness Solving the 3D structure (Schmidt et al. 2016) of the receptor was first confirmed by the lack of effect provided a further unexpected finding. σ1R does not have, of opioid receptor antagonists and, secondly, by cloning as previously hypothesized, two transmembrane domains and discovering that it was not a GPCR. Solving of 3D and extracellular C- and N-terminal domains, but an structure (see details below) has confirmed some of the extracellular N-terminal end, a transmembrane α–helical assumptions about these receptors and has provided domain and a C-terminal tail having a cupin-like β-barrel brand new information related to atypical membrane with a buried ligand-binding site. Adjacent molecules insertion and oligomeric (trimeric) structure. show a homo-oligomeric arrangement consisting of three closely interacting σ1R protomers. Despite homology (relatively poor) with a fungal sterol isomerase (Cobos Evidence for a relevant role of R on σ1 et al. 2008), no catalytic activity has been yet allocated cocaine addiction to σ1R. SKF-10,047 displays psychomimetic activity while it does σ1R may interact with receptors for a variety of not selectively bind to μ- or k-opioid receptor. Although hormones/neurotransmitters (see below and Fig. 2), thus it was firstly assumed that the compound could bind to raising the hypothesis that the receptor could regulate the a novel opioid receptor (Martin et al. 1976), its effect was expression and/or the function of cell-surface receptors. not blocked by nonselective opioid receptor antagonists Kruse recently reviewed the intriguing features of this (Vaupel 1983). The compound in fact binds to σ1R protein that shows no structural resemblance with whose cloning showed that it does not have the seven any other membrane