Aripiprazole in an Animal Model of Chronic Alcohol Consumption and Dopamine D₂ Receptor Occupancy in Rats

Abstract

Background: Epidemiologic studies and clinical assessment of schizophrenic population have revealed a high incidence of overlap between schizophrenia and addictive disorders. Objective: The aim of the present investigation was to study the effect of aripiprazole in a preclinical animal model of chronic alcohol self-administration (CASA) and also to evaluate the influence of CASA on plasma pharmacokinetics and dopamine D₂ receptor (D₂R) occupancy in rats. Methods: The effect of oral administration of aripiprazole (1, 3, and 10 mg/kg) on 4% alcohol intake in CASA was studied for a period of 45 min after a post-dosing interval of 60 min. Brain penetration, pharmacokinetics, and D₂R occupancy of aripiprazole were evaluated in normal and CASA rats. Results: Aripiprazole reduced alcohol consumption in CASA rats by 13, 28, and 86% at 1, 3, and 10 mg/kg, respectively, and the effect reached statistical significance at 10 mg/kg (p < .01). At this behavioral effective dose, a decrease (75%) in total plasma apparent clearance and an increase in oral area under the concentration–time curve (3.98-fold) and bioavailability (3.50-fold) of aripiprazole was observed in CASA rats. Striatal D₂R occupancy and brain exposure of aripiprazole were significantly higher (∼twofold) in CASA rats when compared to normal rats (p < .01). Conclusion: Chronic alcohol intake results in a significant increase in exposure of aripiprazole in plasma and brain and striatal D2R occupancy. Scientific significance: Chronic alcohol intake would increase aripiprazole exposure, thus aripiprazole dose might have to be decreased (assuming this same phenomenon occurs in humans).

• alcohol abuse
• aripiprazole
• dopamine D₂ receptor occupancy
• pharmacokinetics
• psychotic disorders
• schedule-induced ethanol polydipsia