Regulation of striatal tyrosine hydroxylase phosphorylation by acute and chronic haloperidol.
The typical neuroleptic haloperidol increases the state of phosphorylation and activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines. Here we show that the increases in TH phosphorylation produced by haloperidol at Ser31 and Ser40, two sites critically involved in the regulation of enzymatic activity, are abolished in dopamine D2 receptor-null mice and mimicked by the selective dopamine D2 receptor antagonist, eticlopride. Moreover, the ability of haloperidol and eticlopride to stimulate phosphorylation at both seryl residues is prevented by treatment with SL327, a compound that blocks activation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). We also show that chronic administration of haloperidol reduces the basal levels of phosphoSer31-TH and decreases the ability of the drug to stimulate Ser40 phosphorylation. These results provide a model accounting for the stimulation exerted by haloperidol on dopamine synthesis. According to this model, haloperidol increases TH activity via blockade of dopamine D2 receptors, disinhibition of dopaminergic projection neurons and ERK1/2-dependent phosphorylation of TH at Ser31 and Ser40. These studies also show that lower levels of phosphorylated TH are associated with chronic neuroleptic treatment and may be related to depressed dopaminergic transmission in nigrostriatal neurons.
Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden.
Kerstin
K
Håkansson
Laura
L
Pozzi
Alessandro
A
Usiello
John
J
Haycock
Emiliana
E
Borrelli
Gilberto
G
Fisone
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000172:deficiency / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D017448:Receptors, Dopamine D2; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol