Tyrosine hydroxylase mRNA and protein are down-regulated by chronic clozapine in both the mesocorticolimbic and the nigrostriatal systems.
The dopaminergic system is one of the most important targets for pharmacological treatment of schizophrenia. Despite substantial work on mechanisms of action, it is not clear which dopaminergic pathways mediate the therapeutic effects of antipsychotic drugs. It has been shown that chronic clozapine, an atypical antipsychotic, decreases dopamine levels in the mesocorticolimbic system but not in the nigrostriatal system. Because tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of dopamine, we studied the effect of chronic clozapine in both dopaminergic systems. We demonstrated a decrease of tyrosine hydroxylase mRNA not only in the ventral tegmental area but also in the substantia nigra, the cell body areas of the mesocorticolimbic and the nigrostriatal systems, respectively. The reduced tyrosine hydroxylase mRNA level in these areas is accompanied by an ample reduction in the tyrosine hydroxylase protein level in their corresponding axonal terminal fields, the nucleus accumbens and the striatum. There was thus discordance between the clozapine-induced decrease of tyrosine hydroxylase mRNA and protein and the absence of an effect on dopamine levels in the nigrostriatal system. It has been suggested that reduced levels of dopamine in the mesocorticolimbic system are required for the antipsychotic effect of the drug. Therefore, the modulation of tyrosine hydroxylase gene expression by clozapine in the mesocorticolimbic system might be necessary for its antipsychotic effect; this effect might be of relevance when considering new atypical agents.
Tejedor-Real
Purificación
P
CNRS UMR 7091, L.G.N. Bâtiment Cervi, Hôpital de la Pitié-Salpêtrière, Paris, France.
Faucon Biguet
Nicole
N
Dumas
Sylvie
S
Mallet
Jacques
J
D000818:Animals; D003024:Clozapine / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D008032:Limbic System / Q000187:drug effects / Q000201:enzymology; D008297:Male; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000201:enzymology
D011506:Proteins; D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase; D003024:Clozapine