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Regulation of striatal tyrosine hydroxylase phosphorylation by acute and chronic haloperidol
Author(s) -
Håkansson Kerstin,
Pozzi Laura,
Usiello Alessandro,
Haycock John,
Borrelli Emiliana,
Fisone Gilberto
Publication year - 2004
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2004.03547.x
Subject(s) - eticlopride , tyrosine hydroxylase , dopaminergic , haloperidol , phosphorylation , dopamine , dopamine receptor , chemistry , medicine , endocrinology , kinase , pharmacology , biology , biochemistry , sch 23390
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 D 2 receptor‐null mice and mimicked by the selective dopamine D 2 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 D 2 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.