Novel Dopamine agents to REduce impulsivity and drinking behavior in animal models of alcohol Use disorder

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Fredriksson I1, Newman A2, Wirf M1, Jayaram-Lindström N1, Steensland P1

1Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research & Education, Stockholm, Sweden
2National Institute of Drug Abuse, National Institute of Health, Baltimore, Maryland, USA

Alcohol use disorder (AUD) is associated with a dysregulated dopamine system modulating e.g. reward, craving and impulsivity. The so-called “monoamine stabilizer” (-)-OSU6162 (OSU; developed by Nobel Laureate Arvid Carlsson) is suggested to attenuate or stimulate dopamine functioning depending on the prevailing dopaminergic tone (potentially by antagonizing postsynaptic D2 and presynaptic D2 autoreceptors, respectively) and thus has potential as a novel AUD medication. Indeed, we recently showed that OSU attenuates voluntary drinking, alcohol seeking, and cue/priming-induced reinstatement in long-term drinking rats. Furthermore, OSU counteracts a dopamine deficit state in the nucleus accumbens of long-term drinking rats. These preclinical findings were recently supported by our “proof-of-concept” human laboratory study in alcohol dependent patients, where OSU, compared to placebo, significantly attenuated priming-induced craving and induced significantly lower subjective “liking” of the consumed alcohol. Exploratory analyses showed that the effect of OSU was driven by those individuals with higher level of baseline impulsivity. Based on the selective results in individuals with high baseline impulsivity, the present study aimed to investigate the effects of OSU on motor impulsivity using the 5-Choice Serial Reaction Time Task (5CSRTT) in long-term drinking as well as alcohol-naïve Wistar rats. We also compared the effects of OSU to the selective D3-antagonist PG01037. Following the training period, a prolonged waiting period (i.e. an inter-trial-interval of seven instead of five seconds) was applied to induce premature responses (an indicator of impulsive behavior in the 5CSRTT). The pretreatment with the high OSU dose (30 mg/kg) significantly decreased the number of premature responses in both drinking and alcohol-naïve rats whereas the D3-antagonist PG01037 had no significant effects. These results indicate that D2, in favor of D3 receptors, are involved in regulating the measured premature responding. Furthermore, the results indicate that OSU also might have potential to improve dysregulated impulse control in addition to the previously found ability to attenuate alcohol-mediated behaviors. In conclusion, these results support further evaluation of OSU with regards to the effects on alcohol use outcomes and the potential beneficial effects in subgroup of alcohol dependent individuals (e.g. those with high level of impulsivity).