Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary.
[3H]Spiperone-binding assay to D2 receptors and quantitative ribonuclease protection assay for both isoforms (D2L and D2S receptor) of the D2 receptor mRNA and the prolactin mRNA were performed on pituitaries from the control rat and from the rat injected orally daily with either haloperidol (2 mg/kg) or aripiprazole (24 mg/kg) for 21 days. Haloperidol treatment increased the [3H]spiperone-binding by 28%, the levels of D2L and D2S receptor mRNA by 41% and 38%, respectively, and the level of prolactin mRNA by 26%. In contrast, the treatment with aripiprazole, a newly developed atypical antipsychotic with reduced side effects, decreased the [3H]spiperone-binding by 24% and the levels of D2L and D2S receptor mRNA by 23% and 23%, respectively, and did not have any effect on the level of prolactin mRNA. The same treatment with sulpiride (100 mg/kg) increased the levels of D2L and D2S receptor mRNA by 59% and 62%, respectively, but treatment with clozapine (25 mg/kg) did not cause any effect. Neither treatment changed the ratio of the level of D2S receptor mRNA to the level of D2L receptor mRNA in the pituitary. These findings indicate that D2 receptor densities in the pituitary are influenced differentially by the treatment with these antipsychotics, which could be induced at least partly by the changes in the levels of mRNA without any effects on the splicing mechanisms and thus affect the plasticity of the prolactin mRNA expression. The inhibitory effects of chronic aripiprazole treatment on D2 receptors in the pituitary might underlie this drug's clinical property of reduced hyperprolactinemia side effect.
Inoue
A
A
Department of Pharmacology, Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine, Hiroshima 734, Japan. ainoue@ipc.hiroshima-u.ac.jp
Seto
M
M
Sugita
S
S
Hide
I
I
Hirose
T
T
Koga
N
N
Kikuchi
T
T
Nakata
Y
Y
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology; D000068180:Aripiprazole; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D011388:Prolactin / Q000096:biosynthesis / Q000235:genetics*; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000235:genetics*; D012260:Ribonucleases / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism
D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D013134:Spiperone; D000068180:Aripiprazole; D011388:Prolactin; D012260:Ribonucleases; D006220:Haloperidol