The overall decrease in consummatory drive seen in

The overall decrease in consummatory drive seen in rodents treated with naltrexone in previous studies is in accordance with the effects seen with mice treated with SNAP 37889 in this study. While it may seem inappropriate to use a broad-acting drug like SNAP 37889 that suppresses overall consummatory drive for AUD therapy, current therapeutics like naltrexone show similar effects in rodents and are used clinically for the management of heroin addiction (Martin et al., 1973) and AUD (Volpicelli et al., 1995). Studies have shown that opioid agonists have broad effects on the control of feeding and drinking (Mucha and Iversen, 1986, Sanger and Mccarthy, 1981), and that opiate antagonists like naloxone and naltrexone can decrease food and water intake in a number of species (i.e. rats, mice and guinea pigs) under a variety of experimental situations (Brown and Holtzman, 1979, Frenk and Rogers, 1979, Sanger et al., 1981, Schulz et al., 1980). Likewise, consumption of an ethanol solution is potentiated by morphine or opioid agonists (Hubbell et al., 1986, Zhang and Kelley, 2002) and attenuated by naloxone and naltrexone (Hubbell et al., 1986, Stromberg et al., 1998). Furthermore, opioid receptor antagonists have been shown to decrease consumption of both sucrose and saccharin solutions (Beczkowska et al., 1992, Beczkowska et al., 1993, Kelley et al., 1996). The similar effects observed with previous studies using clinically approved naltrexone (Levine et al., 1985) and the current study using SNAP 37889 further demonstrates the therapeutic value of targeting GAL3. One possible explanation for the reduction in ethanol consumption following SNAP 37889 treatment could be due to altered metabolism of ethanol by blocking GAL3 located in the liver. Blood ethanol concentration is established by how quickly ethanol is absorbed (primarily from the small intestine), distributed, metabolised by HC-030031 in the liver (primarily by ALDH and ADH), and then excreted (Zakhari, 2006). GAL3 antagonism by SNAP 37889 does not appear to interfere with liver enzyme function, as the SNAP 37889 treated mice had the same metabolic capability as vehicle treated mice. Consequently, this supports the hypothesis that SNAP 37889 most likely acts centrally to reduce ethanol intake. To our knowledge, the effect of GAL3 antagonism on morphine intake has not been explored. However, there is a degree of cross-over for therapeutics against AUD and heroin addiction, and we were therefore drawn to examine the effect of SNAP 37889 on morphine self-administration and relapse-like behaviour. While vehicle treated mice reliably maintained self-administration of morphine, this behaviour was noticeably reduced upon SNAP 37889 treatment. The efficacy of SNAP 37889 was even more evident during the PR schedule which showed that the motivation to seek out opioids was markedly reduced following treatment with this GAL3 antagonist. While SNAP 37889 did not impact cue-induced ‘relapse’ at this dose, the decrease in morphine self-administration supports the proposition that GAL3 is involved in modulating opioid intake. The lack of SNAP 37889 to impact cue-induced relapse for morphine despite being effective in preventing cue-induced relapse for alcohol in previous studies (Ash et al., 2014) may reflect differences in the underlying neurochemistry involved in mediating relapse in these distinct drugs of abuse and the different paradigms employed. For instance, rats previously underwent extinction via removal of cues prior to reinstatement to alcohol whereas the current study in mice assessed morphine-seeking following abstinence rather than extinction. In addition, we only examined one dose of SNAP 37889 (30 mg/kg) throughout these studies. This dose was based on previous pilot studies in mice that showed this dose to be effective at reducing alcohol consumption using the SHAC paradigm, while other doses failed to show a significant effect. While it is plausible that different doses of SNAP 37889 could have varying impacts on different models and phases of the addiction cycle, higher doses of the drug could also result in off-target effects through loss of pharmacological selectivity and also possibly non-specific motor impairments that could potentially confuse interpretation of the results.