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  • Galanin mediates its activity by binding to three

    2022-05-17

    Galanin mediates its activity by binding to three G-protein coupled receptor subtypes (designated GAL1-GAL3). Since GAL3 mRNA is found mainly in regions of the mesolimbic dopamine system, such as the ventral tegmental area, dorsal raphe nucleus, LC, amygdala, hippocampus, thalamus, hypothalamus, NAc, and pre-frontal cortex (Hawes and Picciotto, 2004, Kolakowski et al., 1998), it was believed that specifically targeting GAL3 may regulate the motivation to seek drugs (Branchek et al., 2000). Belfer and colleagues found a haplotype association between AUD and galanin in Finnish Caucasians and Plains American Indians, two ethnically remote human populations (Belfer et al., 2006) and further determined that GAL3, but not the GAL1 or GAL2 receptors, contributed to vulnerability to alcoholism (Belfer et al., 2007). While information is somewhat limited on the interface between galanin and opioids, both morphine administration and withdrawal stimulates galanin expression in the LC of mice and the presence of Fruquintinib galanin decreases signs of withdrawal (Holmes et al., 2012). This effect was proposed to work through GAL1, as GAL1 knockout mice experienced more severe withdrawal symptoms than GAL2 knockout mice when compared to littermate controls (Holmes et al., 2012). To our knowledge, opiates and GAL3 have not yet been explored, however since GAL1 and GAL3 have similar downstream effects, it was postulated that targeting GAL3 may be beneficial in identifying possible therapeutics for drugs of abuse. The development of small molecule, blood brain barrier penetrating antagonists selective for the GAL3 receptor (Swanson et al., 2005) has provided an opportunity to study central galanin physiology. SNAP 37889, and its analog SNAP 398299, are highly selective for GAL3 over GAL1 and GAL2 and bind with high affinity to cells expressing human GAL3 (Swanson et al., 2005). We have already shown that administration of SNAP 37889 reduces operant responding for alcohol (Ash et al., 2011), diminishes the motivation to consume alcohol and attenuates cue-induced reinstatement of alcohol seeking in iP rats (Ash et al., 2014). The present study therefore aimed to further elucidate the role of GAL3 in binge drinking and morphine self-administration in mice. We investigated the effect of SNAP 37889 in a binge drinking model by adapting the Scheduled High Alcohol Consumption (SHAC) procedure (Finn et al., 2005, Tanchuck et al., 2011). The SHAC paradigm allows alcohol preferring mice (C57BL/6J) to drink to blood ethanol concentrations that can have quantifiable effects on behaviour and physiology, >1.0 mg ethanol/ml blood (Rhodes et al., 2005) an equivalent effect to what is seen in humans. Given the high density of GAL3 in the hypothalamus, this receptor may be related to the modulation of feeding. Indeed, GAL3 has been shown to play a role in caloric rich ethanol intake, which supports the hypothesis that GAL3 is involved in modulation of appetite and feeding. We wanted to investigate whether targeting GAL3 had a generalised effect on feeding related systems or was specific to alcohol. We therefore examined the ability of SNAP 37889 to reduce the intake of two naturally rewarding solutions, sucrose and saccharin. Like ethanol, sucrose has a calorific value, whereas saccharin is non-calorific (Wiet and Beyts, 1992) so it was of interest to compare preference for all solutions. Opioids are generally not administered orally and have no calorific content, hence investigating the potential of this GAL3 antagonist to decrease use of other drugs of abuse like morphine will help assess the role of the GAL3 receptor in drug-seeking independent of effects on palatability. To fully characterise the effects of SNAP 37889, various behavioural paradigms were used to assess for differences in motor co-ordination, locomotor activity and anxiety. SNAP 37889 was also assessed for intrinsic rewarding properties using the conditioned place preference paradigm.