title: Agonist and antagonist effects of aripiprazole on D₂-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone.
abstract: BACKGROUND
  The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D₂ receptors, where its degree of efficacy as a partial agonist remains controversial.
  
  
  METHODS
  We examined the properties of aripiprazole at D₂-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2 mM K(+), low dopaminergic tone) and a stimulated condition (15 mM K(+), where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions.
  
  
  RESULTS
  Aripiprazole under the basal condition acted as an agonist at D₂-like autoreceptors and fully activated them at about 10 nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D₂-like autoreceptor activation. Under the stimulated (15 mM K(+)) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole.
  
  
  CONCLUSIONS
  Under high dopaminergic tone, aripiprazole acts as a D₂-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D₂-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D₂R ligand.
authors.affiliation: Neuroscience Institute and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Guo Fen
authors.initials: GF
authors.lastname: Ma
authors.affiliation: Neuroscience Institute and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Noora
authors.initials: N
authors.lastname: Raivio
authors.affiliation: Neuroscience Institute and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Sabrià
authors.affiliation: Neuroscience Institute and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain. Jordi.Ortiz@uab.cat.
authors.forename: Jordi
authors.initials: J
authors.lastname: Ortiz
mesh_terms: D000818:Animals; D000068180:Aripiprazole / Q000494:pharmacology*; D017660:Autoreceptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis*; D018491:Dopamine Agonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*
chemical_list: D017660:Autoreceptors; D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D010880:Piperidines; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D000068180:Aripiprazole; C026539:preclamol; D011188:Potassium; D004298:Dopamine
keywords: GPCR; intrinsic activity; intrinsic efficacy; schizophrenia; striatum