The role of the dopamine system in the ability of (-)-OSU6162 to reduce voluntary alcohol drinking and binge-eating in the rat

Sammanfattning: BACKGROUND AND AIMS: The dopamine system is involved in the reinforcing effects of both food and alcohol and is thus a potential treatment target for alcohol use disorder (AUD) and binge-eating disorder (BED). Alcohol use disorder is characterized by difficulties to control alcohol drinking and by drinking despite adverse consequences. Few pharmacological treatments are available and their efficacies are limited. The monoamine-stabilizer (-)-OSU6162 has been identified as a potential novel treatment for AUD by showing that it reduces alcohol drinking, alcohol seeking, relapse to seeking and withdrawal symptoms in long-term drinking rats (Steensland et al, 2012). In the present thesis, the possible underlying mechanisms in the ability of (-)-OSU6162 to reduce alcohol drinking were investigated. Binge eating disorder is characterized by episodes of eating large amounts of foods in a relatively short amount of time, the difficulty to control binge-eating and feelings of shame and guilt. Recently, lisdexamfetamine was approved for the treatment of BED. Here, the potential of (-)-OSU6162 as a treatment for BED was investigated. METHODS: Rats were drinking in the two-bottle choice intermittent-access to 20% ethanol (IA20E) paradigm for three to ten months. The effects of long-term voluntary alcohol drinking on dopamine D2 receptor (D2R) expression (paper I) and dopamine output (paper II) in the nucleus accumbens (NAc) were investigated using qPCR and proximity ligation assay microdialysis. The effects of (-)-OSU6162 on dopamine in the NAc in longterm drinking rats were investigated using microdialysis (paper II). Pharmacological antagonists were used to study the role of the D2R and the serotonin 5-HT2A receptor in the ability of (-)-OSU6162 to reduce alcohol drinking (paper III). Using a model of binge-eating and the second-order schedule of reinforcement, the effects of (-)-OSU6162 on binge-like eating and cue-controlled seeking for chocolate-flavored sucrose were evaluated (paper IV). RESULTS: Long-term voluntary alcohol drinking downregulated dopamine levels, D2R expression levels and D2R-D2R homoreceptor complexes, and increased adenosine A2ARD2R heteroreceptor complexes in the NAc. Moreover, alcohol drinking reduced the dopamine response to an alcohol challenge. (-)-OSU6162 increased dopamine levels in the NAc and normalized the dopamine response to an alcohol challenge. Pre-treatment with a 5-HT2A antagonist, but not a D2 antagonist, prevented the ability of (-)-OSU6162 to reduce voluntary alcohol intake. (-)-OSU6162 reduced binge-like eating and seeking (second-order schedule of reinforcement) of palatable food. Furthermore, (-)-OSU6162 infused into the NAc core reduced food seeking. CONCLUSIONS: (-)-OSU6162 counteracted the dopaminergic downregulations induced by long-term alcohol intake. This effect, together with partial agonism at the 5-HT2A receptor might be involved in the effects of (-)-OSU6162 to reduce voluntary alcohol intake. (-)-OSU6162 affected behaviors relevant to BED, indicating the potential of (-)-OSU6162 as a novel treatment for BED