THE MONOAMINE STABILIZER (-)-OSU 6162-A POTENTIAL NOVEL TREATMENT FOR ALCOHOL USE DISORDERS

Alcohol use disorder (AUD) represent a major health problem worldwide. Despite the severe consequences of AUD, only four medications are approved in Sweden for this disease. In addition, the prescription rates are low, partly due to varying clinical efficacy of these medications. Consequently, new, more effective pharmacotherapies are needed. A main problem in the treatment of AUD is the long-lasting vulnerability to relapse. Relapse is typically triggered by: stress, acute exposure to the drug, or drug-associated cues or context. Impaired impulsive control, often seen in AUD individuals, might further contributes to relapse to alcohol drinking. The dopamine (DA) system is one possible treatment target for AUD. Dopamine D2 receptors has been suggested to be involved in mediating alcohol’s reinforcing properties and a decrease in DA release and a reduction in D2 receptors have been found in detoxified AUD patients. This DA down-regulation is hypothesized to induce alcohol craving and contribute to relapse even after a long period of abstinence. In addition to the role of DA in AUD, DA has also been suggested to be involved in impulse behavior. The monoamine stabilizer (-)-OSU6162 (OSU6162) has the ability to stimulate, inhibit, or show no effect on DA-related behaviors depending upon the prevailing dopaminergic tone. In this thesis, we evaluated the potential of OSU6162 as a new treatment for AUD using validated preclinical models of behaviors related to AUD. We have, in this thesis, identified OSU6162 as a potential novel treatment for AUD. Using a battery of animal models, we showed that OSU6162 attenuated voluntary alcohol intake, alcohol withdrawal symptoms (tail stiffness and walking with broad gait), the motivation to seek alcohol, cue/priming-induced reinstatement (relapse) of alcohol seeking, and relapse-like drinking in in rats that had been drinking alcohol for a long period of time. Moreover, we showed that OSU6162 pretreatment improved motor impulsivity in both alcohol and alcohol-naïve rats. Furthermore, OSU6162 did not induce conditioned place preference in either alcohol-naïve rats or rats that had been drinking alcohol before the experiment, indicating that OSU6162 does not possess any abuse liability on its own. Together these results highlights OSU6162’s potential to prevent relapse triggered by alcohol craving, alcohol related cues, re-exposure to alcohol and or an urge to relieve abstinence symptoms. In addition, the improved impulse control following OSU6162 treatment might help AUD individuals to override a compulsive drugtaking behavior in response to craving and thereby possibly prevent relapse to alcohol drinking. In addition to the global health problems related to alcohol, an opioid addiction epidemic is ongoing in the United State. We therefore decided to examine the potential of OSU6162 to attenuate self-administration of the opioid oxycodone in rats. The results showed that OSU6162 attenuated operant oxycodone self-administration but had no effect on context-induced reinstatement, at least in the dose tested. These preliminary results indicate that OSU612 might have potential to decrease intake of oxycodone, however, further studies are needed to fully evaluate the potential of OSU6162 on oxycodone self-administration and reinstatement. In conclusion, the results in this thesis indicate that OSU6162 may serve as a novel treatment for AUD and provided the necessary rational for a clinical “proof-ofconcept” study with OSU6162 in alcohol dependent patients. The clinical study was successfully executed and supported our preclinical findings by showing that OSU6162 attenuated alcohol craving in alcohol dependent patients. Thus, the rapid and fruitful transition of OSU6162 from bench to clinic highlights the importance of the preclinical medication development program used in this thesis work. LIST OF SCIENTIFIC PAPERS I. Steensland P, Fredriksson I, Holst S, Feltmann K, Franck J, Schilström B, and Carlsson A (2012). The dopamine stabilizer (-)-OSU6162 attenuates voluntary ethanol intake and ethanol-induced dopamine output in the nucleus accumbens. Biological Psychiatry, 72: 823-831. II. Feltmann K*, Fredriksson I*, Wirf M, Schilström B and Steensland S (2015). The Monoamine Stabilizer (-)-OSU6162 Counteracts DownRegulated Dopamine Output in the Nucleus Accumbens of Long-Term Drinking Wistar Rats. Addiction Biology, 21: 1130-1140. *These authors contributed equally III. Fredriksson I, Wirf M, Carlsson A and Steensland P. The Monoamine Stabilizer (-)-OSU6162 Prevents the Alcohol Deprivation Effect and Improves Motor Impulsive Behavior in Rat. Manuscript. IV. Fredriksson I, Bonci A and Steensland P. Evaluation of the Monoamine Stabilizer (-)-OSU6162 on Oxycodone Self-administration and ContextInduced Reinstatement in Rat. Manuscript. CONTENTS