title: 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).
  
  
  CONCLUSIONS
  Chronic alcohol intake results in a significant increase in exposure of aripiprazole in plasma and brain and striatal D₂R occupancy.
  
  
  CONCLUSIONS
  Chronic alcohol intake would increase aripiprazole exposure, thus aripiprazole dose might have to be decreased (assuming this same phenomenon occurs in humans).
authors: Department of ADME, Discovery Research, Suven Life Sciences Ltd ., Hyderabad - 500055, India. nvsrk@suven.com
authors: Ramakrishna
authors: R
authors: Nirogi
authors: Vishwottam
authors: V
authors: Kandikere
authors: Pradeep
authors: P
authors: Jayarajan
authors: Gopinadh
authors: G
authors: Bhyrapuneni
authors: Ramanatha
authors: R
authors: Saralaya
authors: Nageswararao
authors: N
authors: Muddana
authors: Renny
authors: R
authors: Abraham
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000068180:Aripiprazole; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D023421:Models, Animal; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012646:Self Administration
chemical_list: D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D017448:Receptors, Dopamine D2; D000068180:Aripiprazole