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  • Introduction The first reference to a possible

    2020-10-26

    Introduction The first reference to a possible involvement of orexins in the effects of drugs of abuse appeared in 2003 and showed that orexigenic peptide neurons respond to the chronic administration of morphine followed by abrupt withdrawal symptoms caused by opioid receptor antagonists (Georgescu et al., 2003). Subsequent studies examined the effect of orexigenic peptides in the reward mechanism associated with consumption of drugs of abuse. It is today accepted that orexins have an important role in responses associated with both food and drug rewards (Aston-Jones et al., 2010; Harris et al., 2005). The exact nature of the effects of orexins in this context is unknown because of their complex involvement in different aspects of drug addiction, aversive or appetitive motivation, interactions with Pavlovian or instrumental learning processes and induced hedonic states. Stress and drug addiction correlate in advanced societies. Therefore, the mechanisms of stress and of reward must be interconnected. A relevant regulator of stress responses is the corticotropin releasing factor (CRF), which is one of the main players in the hypothalamic–pituitary–adrenal (HPA) axis (Gallagher et al., 2008). CRF is a peptide synthesized and secreted by hypophysiotropic neurons that, in response to stress, is released into the hypophyseal portal veins that give access to the anterior pituitary gland. Therefore, CRF activates its cognate receptors and induces the release of the nk1 receptor into the systemic circulation, where it travels to its main target, the adrenal gland. ACTH stimulates the synthesis and secretion of glucocorticoids in the adrenal cortex (Bamberger et al., 1996). In fact, the actions of glucocorticoids are mediated by glucocorticoid (GR) and mineral corticoid (MR) receptors, that are widely expressed in the brain, including areas involved in emotion, memory, and behavior such as the septum, hippocampus, and prefrontal cortex (Morimoto et al., 1996; Viengchareun et al., 2007). Sigma 1 receptors (σ1R) are an atypical type of membrane receptors whose exact function is not known. They have been proposed as mediators of pluripotent modulation in living cells (Su et al., 2016) and research on this protein is gaining momentum due to its potential as target to combat neuropathic pain (Corbera et al., 2006; Mei and Pasternak, 2002; Sun et al., 2016). In fact, the three-dimensional structure has been recently elucidated. σ1R protomers, with a single transmembrane domain and a C-terminal tail having a cupin-like β-barrel with a buried ligand-binding site, arranged into homotrimers (Schmidt et al., 2016). Interestingly, it is a target of different drugs of abuse, cocaine and methamphetamine among them (Cobos et al., 2008; Nguyen et al., 2005). Due to the reports showing that σ1R may interact with metabotropic receptors for a variety of hormones/neurotransmitters, it was tempting to speculate that the receptor may be regulating the expression and function of GPCRs and of GPCR heteromers. As σ1R may form heteromers with corticotropin-releasing factor CRF1 receptor (Navarro et al., 2015), the occurrence of σ1R-containing heteroreceptor complexes and the effect of amphetamine on orexin-CRF heteromer-mediated signaling.
    Results
    Discussion The results here presented are evidence of a novel interaction involving two GPCRs, OX1R and CRF2R, in both heterologous expression systems and natural sources. Two allosterically-mediated specific properties of this heteroreceptor complex were i) a blockade by CRF of OX1R signaling and ii) a cross-antagonism, which was instrumental to detect the heteromers even in living animals. A review on the uniqueness of GPCR heteromers as example of the ability of antagonists of one protomer to antagonize the signaling of another protomer in an heteroreceptor complex is provided elsewhere (Franco et al., 2016). The structure of complexes formed by GPCRs and coupled G proteins is instrumental for heteromer-function (Cordomí et al., 2015). The negative modulation of the effect of Orexin A by CRF suggests that some of the effects of Orexin A on the HPA (Spinazzi et al., 2006; Steiner et al., 2013) occur at the level of receptors forming heteromers in brain cells. Our results also constitute an underlying framework to address therapeutic approaches to combat stress-related psychiatric disorders in which the hypocretin/orexin system has a relevant role (reviewed in (James et al., 2017)). It should be noted that the expression of the orexin receptor has been characterized in cells of the HPA axis (Czerwinska et al., 2017). We also demonstrate that amphetamine modulates both OX1R and CRF2R-mediated signaling and that the effect of the drug was mediated by sigma receptors forming heteromers with OX1R and CRF2R. The overall mechanism constitutes an example of cytocrin signaling that may underlie both short-term and long-term transcription-mediated events (Navarro et al., 2017).