The monoamine stabilizer (-)-OSU6162 counteracts downregulated dopamine output in the nucleus accumbens of long-term drinking Wistar rats

We recently established that the monoamine stabilizer (-)-OSU6162 (OSU6162) decreased voluntary alcohol-mediated behaviors, including alcohol intake and cue/priming-induced reinstatement, in long-term drinking rats, while blunting alcohol-induced dopamine output in the nucleus accumbens (NAc) of alcohol-naive rats. Therefore, we hypothesized that OSU6162 attenuates alcohol-mediated behaviors by blunting alcohol's rewarding effects. Here, we evaluated the effects of long-term drinking and OSU6162 treatment (30mg/kg, sc) on basal and alcohol-induced (2.5g/kg, ip) NAc dopamine outputs in Wistar rats after 10months of intermittent access to 20% alcohol. The results showed that basal and alcohol-induced NAc dopamine outputs were significantly lower in long-term drinking rats, compared with alcohol-naive rats. In the long-term drinking rats, OSU6162 slowly increased and maintained the dopamine output significantly elevated compared with baseline for at least 4hours. Furthermore, OSU6162 pre-treatment did not blunt the alcohol-induced output in the long-term drinking rats, a finding that contrasted with our previous results in alcohol-naive rats. Finally, OSU6162 did not induce conditioned place preference (CPP) in either long-term drinking or alcohol-naive rats, indicating that OSU6162 has no reinforcing properties. To verify that the CPP results were not due to memory acquisition impairment, we demonstrated that OSU6162 did not affect novel object recognition. In conclusion, these results indicate that OSU6162 attenuates alcohol-mediated behaviors by counteracting NAc dopamine deficits in long-term drinking rats and that OSU6162 is not rewarding on its own. Together with OSU6162's beneficial side-effect profile, the present study merits evaluation of OSU6162's clinical efficacy to attenuate alcohol use in alcohol-dependent patients.