inspire you In order to ensure that the decrease
In order to ensure that the decrease in ethanol and morphine intake was not due to a sedative effect of SNAP 37889, locomotor activity and motor learning were assessed through behavioural paradigms. Using the locomotor test, SNAP 37889 did not alter any parameters of locomotion; this lack of sedation was also seen in a previous study using iP rats treated with SNAP 37889 (Ash et al., 2011). Furthermore, SNAP 37889 did not cause motor dysfunction or interfere with motor learning on a rotarod. All measures of locomotor activity and motor coordination suggest that the motor pathways were not affected by SNAP 37889. Taken together these data suggest that the ability of SNAP 37889 to decrease ethanol and morphine intake is not due to sedative or motor impairment.
Effective therapeutics should not themselves be rewarding due to risk of addiction, so an important area of inquiry was to determine if the effects of SNAP 37889 in attenuating drug abuse arose from intrinsically rewarding effects of GAL3 antagonism. In mice, there was no significant difference in time spent in the SNAP 37889 paired zone compared to the vehicle paired zone, showing that GAL3 antagonism does not lead to conditioned incentive properties or aversive effects.
A large body of literature attests to a high co-morbidity between drug addiction and mood disorders including depression (Myers et al., 1984, Robins and Regier, 1991, Rounsaville et al., 1982) and anxiety (Degenhardt et al., 2001, Merikangas et al., 1998). Blackburn and colleagues reported that a range of different inspire you and indolone GAL3 antagonists could be used to treat depression and/or anxiety. They showed that these compounds could enhance the mobility, climbing and swimming behaviour in rats in the forced swim test and increase time spent interacting in a social interaction test (Blackburn et al., 2003). Of the compounds studied, 3-imino-2-indolones, such as SNAP 37889, were shown to have the highest GAL3 binding affinities (Konkel et al., 2006). Subsequent studies have revealed considerable variation in these effects of GAL3 antagonists on anxiety and/or depression, which seems to be sensitive to the species studied, the dose employed and the route of administration (Barr et al., 2006, Lundstrom et al., 2008, Swanson et al., 2005). Some of these results are consistent with the current findings that SNAP 37889 has minimal to no impact on anxiety-like behaviour in mice, as seen during the light/dark test. Our previous studies on the effect of SNAP 37889 on anxiety-like behaviour also showed no significant difference between SNAP 37889 and vehicle treated groups in the light/dark test or elevated plus maze in iP rats (Ash et al., 2011).
Conclusions Using the GAL3 antagonist, SNAP 37889, we have explored the role of GAL3 in drug-seeking behaviour in mice. We show that GAL3 antagonism decreases generalised consummatory behaviour, including ethanol, sucrose and saccharin consumption, and highlight that the decrease in calorie containing sucrose and ethanol intake seems to be more influenced by SNAP 37889. Our work suggests that SNAP 37889 interrupts the positive feedback loop between drugs of abuse and galanin. This study also provides evidence for the ability of SNAP 37889 to decrease ethanol drinking and morphine self-administration without affecting locomotion, motor control, anxiety or conditioned place preference. Our data shows that the decrease in ethanol consumption upon SNAP 37889 treatment is not related to hepatic metabolism, supporting a centrally mediated effect upon GAL3 signalling. Future studies assessing drug-seeking behaviour in recently generated GAL3 knockout mice (Brunner et al., 2014) may help to further understand the role of GAL3 in addiction to drugs of abuse.
Conflict of interest
Acknowledgements We thank Dr Bradley Turner for the use of his rotarod and Dr Jhodie Duncan for the use of equipment for the liver assays (The Florey Institute of Neuroscience and Mental Health). This work was funded by the Research Focus Area, Understanding Disease at La Trobe University (awarded to ED) and the Victorian State Government Infrastructure Program. KJS was supported by a La Trobe Postgraduate Scholarship and School of Life Science Postgraduate Publication Award.