The novel antipsychotic aripiprazole is a partial agonist at short and long isoforms of D2 receptors linked to the regulation of adenylyl cyclase activity and prolactin release

• Published in: Brain research Vol. 1003; no. 1-2; pp. 9 - 17
• Main Authors: AIHARA, Koutoku, SHIMADA, Jun, MIWA, Takashi, TOTTORI, Katsura, BURRIS, Kevin D, YOCCA, Frank D, HORIE, Masato, KIKUCHI, Tetsuro
• Format: Journal Article
• Language: English
• Published: London Elsevier 02.04.2004; Amsterdam; New York, NY
• Subjects: Adenylyl Cyclases - metabolism; Animals; Antipsychotic Agents - pharmacology; Aripiprazole; Biological and medical sciences; Cell Line; Dopamine Agonists - pharmacology; Dose-Response Relationship, Drug; Humans; Medical sciences; Mice; Neuropharmacology; Pharmacology. Drug treatments; Piperazines - pharmacology; Prolactin - metabolism; Prolactin - secretion; Protein Binding - drug effects; Protein Binding - physiology; Protein Isoforms - agonists; Protein Isoforms - metabolism; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Quinolones - pharmacology; Rats; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D2 - metabolism; Agonist; Molecular form; Rat; Enzyme; Neuroleptic; Dopamine receptor; Rodentia; Phosphorus-oxygen lyases; Schizophrenia; Lyases; Aripiprazole; In vitro; Adenylate cyclase; Vertebrata; Regulation(control); Mammalia; Cell line; D2 Dopamine receptor; Partial; Prolactin; Animal; Pituitary gland; Release
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2003.09.082

Aripiprazole is a novel antipsychotic with a unique mechanism of action, which differs from currently marketed typical and atypical antipsychotics. Aripiprazole has been shown to be a partial agonist at the D(2) family of dopamine (DA) receptors in biochemical and pharmacological studies. To demonstrate aripiprazole's action as a partial D(2) agonist in pituitary cells at the molecular level, we retrovirally transduced the short (D(2S)) and the long (D(2L)) form of the human DA D(2) receptor gene into a rat pituitary cell line, GH4C1. [(3)H]-raclopride saturation binding analyses revealed a B(max) value approximately four-fold higher at D(2S) receptor-expressing GH4C1 cells than at D(2L) receptor-expressing GH4C1 cells, while a K(d) value was similar. Aripiprazole inhibited forskolin-stimulated release of prolactin in both D(2S) and D(2L) receptor-expressing GH4C1 cells, whereas the maximal inhibition of prolactin release was less than that of DA. Similarly, aripiprazole partially inhibited forskolin-induced cAMP accumulation in both D(2) receptor-expressing cells. Aripiprazole antagonized the suppression attained by DA (10(-7) M) in both D(2) receptor-expressing cells and, at the maximal blockade of cAMP, yielded residual cAMP levels equal to those produced by aripiprazole alone. These results indicate that aripiprazole acts as a partial agonist at both D(2S) and D(2L) receptors expressed in GH4C1 cells. These data may explain, at least in part, the observations that aripiprazole shows a novel antipsychotic activity with minimal potential for adverse events including no significant increase of serum prolactin levels in clinical studies.