Effect of Aripiprazole in an Animal Model of Alcohol Addiction and its Pharmacokinetics and Dopamine D2 Receptor Occupancy in Rats

Drug abuse is a serious health problem in many areas of the world, yet there are no widely effective medications available to treat its underlying pathology or its clinical manifestations. Recent calculations have estimated that drug addiction accounts for more than 40% of the financial cost to society of all major neuropsychiatric disorders. Globally alcohol dependence ranks 3^rd in the list of preventable causes of morbidity and mortality. The aim of present research was to study the effect of aripiprazole in an animal model of alcohol addiction and evaluate its pharmacokinetic, dopamine D₂ receptor occupancy in normal as well as alcohol addicted rats and also substantiate the potential use of aripriprazole in alcohol dependent patients with psychotic disorders. Methods: Male Sprague Dawley (SD) rats were trained to drink 4 % alcohol in a 45 min schedule induced ethanol polydipsia paradigm.  Effects of acute administration of aripiprazole (0, 1, 3 and 10 mg/kg, p.o.) on alcohol addicted rats were studied.  The pharmacokinetic and dopamine D₂ receptor occupancy of aripiprazole were studied in alcohol addicted as well as normal rats.  Results: Aripiprazole dose dependently decreased the alcohol consumption in alcohol addicted rats. The oral bioavailability of aripiprazole at 10 mg/kg, p.o. in alcohol addicted rats and normal rats were 28 and 8 % respectively.  The oral exposure of aripiprazole was found to be 3 fold higher in alcohol addicted rats compared to normal rats.  Acute treatment with aripiprazole at 1 and 3 mg/kg, p.o. had no effect on alcohol drinking in alcohol addicted rats and at a dose of 10 mg/kg, p.o. significantly decreased the alcohol consumption. In normal rats aripiprazole showed 5, 19 & 40 %, in alcohol addicted rats aripiprazole showed 22, 49 & 81 % dopamine D₂ receptor occupancy at dose levels of 1, 3 & 10 mg/kg p.o. respectively.   Conclusion: As reported earlier aripiprazole dose dependently decreased the alcohol consumption.  A significant difference in exposure and dopamine D2 receptor occupancy profile was observed between alcohol addicted rats and normal rats. So care should be taken to monitor the blood levels of aripiprazole in addicted individuals.  Since there is no medication for the specific treatment of dually diagnosed patients with alcohol abuse and mental illnesses such as schizophrenia, schizoaffective disorder and bipolar disorder this study provide further support for the potential therapeutic utility of aripiprazole in alcohol dependent patients with psychotic disorders.