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  • The GAL also modified HT system Millon et al Using


    The GAL(1–15) also modified 5-HT system (Millon et al., 2015). Using a rat medullary raphe-derived cell line RN33B, we observed that GAL(1–15) significantly decreased the 5-HT immunoreactivity in the RN33B Nuclear/Cytosol Fractionation Kit (p<0.001) (Fig. 2). Interestingly this reduction was stronger than the one induced by GAL (p<0.001) (Fig. 2) (Millon et al., 2015). This effect of GAL(1–15) on 5-HT immunoreactivity may indicate a possible mechanism contributing to the depression-like actions of GAL(1–15). In this cell model, we have detected PLA- positive clusters, indicating close proximity of GAL1 and GAL2 receptors and the possible formation of GAL1/GLAR2 heteroreceptor complexes (Millon et al., 2015). Therefore, the formation of GAL1/GAL2 heteroreceptor complexes with high affinities for GAL(1–15) can help explain the fact that GAL(1–15) induces a stronger action than GAL in the reduction of 5-HT in the RN33B. Thus, the strong decrease on 5-HT immunoreactivity induced by GAL(1–15) may indicate a mechanism contributing to the depression- like actions of GAL(1–15) (Fig. 2D) (Millon et al., 2015). Recently, we have described that GAL(1–15) enhances the antidepressant effects induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) acting on 5-HT1A receptors operating as postjunctional or as autoreceptors, confirming the importance of the interaction GALR-5-HT1A receptors (Millon et al., 2016).
    Conclusion All these data emphasized the role of GAL and its N-Terminal fragment (1–15) in depression. Moreover, GAL(1–15) induces a stronger depressive effect than GAL through GAL1-GAL2 heteroreceptor complexes in the raphe-limbic system. Since 5-HT, especially through 5-HT1A, and GAL receptors interact at both pre-and postsynaptic level, the development of drugs targeting potential GAL1-GAL2-5-HT1A heteroreceptor complexes linked to the raphe-hippocampal 5-HT neurons may represent new treatment in depression.
    Acknowledgements This study was supported by grants awarded by Spanish Ministry of Economy (SAF2016-79008-P), and Contratos-puente, Vicerrectorado de Investigación y Transferencia, Universidad de Málaga.
    Introduction According to the National Institutes of Health (National Institute of Mental Health), occasional anxiety caused by worry or fear is a normal emotion. However, in patients with an anxiety disorder, anxiety does not disappear and may worsen over time or interfere with daily activities, such as work, school, and relationships. The classification of anxiety disorders includes separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder, panic disorder, agoraphobia and generalized anxiety disorder (GAD) (American Psychiatric Association, 2013). Despite some limitations, many animal models are used to attempt assessing anxiety in order to understand the neurobiological mechanisms underlying anxiety disorders as well as to discover new targets for the treatment of these heterogeneous conditions (Kalueff et al., 2007, Bouwknecht, 2015). An abundance of evidence suggests that galanin, a neuropeptide widely expressed in the mammalian brain (Melander et al., 1986, Barreda-Gómez et al., 2014, Lang et al., 2015), modulates anxiety-like (Karlsson and Holmes, 2006, Zhao et al., 2013) and depression-like (Kuteeva et al., 2010, Millón et al., 2017) behaviours. Three galanin receptor subtypes mediate the actions of galanin, and they are all G-protein coupled receptors (GPCR). GAL1 and GAL3 are usually coupled to the Gi/0 protein and induce membrane hyperpolarization (Branchek et al., 2000, Smith et al., 1998, Wang et al., 1998). GAL2 is often coupled to Gq/11 and increases intracellular Ca++ (Branchek et al., 2000, Fathi et al., 1998, Wang et al., 1998), though it may also be coupled to Gi/0 (Lang et al., 2015). Galanin receptors regulate the release of several neurotransmitters. For example, galanin decreased glutamate release in the arcuate nucleus of the hypothalamus (Kinney et al., 1998) and in ventral hippocampal slices (Zini et al., 1993). Additionally, galanin raised extracellular levels of noradrenaline in the medial prefrontal cortex (Yoshitake et al., 2013).