Acute and repeated administration of fluphenazine-N-mustard alters levels of tyrosine hydroxylase mRNA in subsets of mesencephalic dopaminergic neurons.
Changes in striatal dopamine turnover and levels of tyrosine hydroxylase messenger RNA were examined in mice injected with D2 selective doses of fluphenazine-N-mustard, an irreversible blocker of dopaminergic receptors. The animals were killed at different times after acute and repeated injections of the drug and dopamine turnover was assessed by measuring dopamine and its metabolite, dihydroxyphenylalanine, in the striatum. Tyrosine hydroxylase mRNA was measured at the single-cell level in neurons of the substantia nigra pars compacta and the ventral tegmental area with quantitative in situ hybridization histochemistry. Acute treatment with fluphenazine-N-mustard induced an increase in both striatal dopamine turnover and the level of tyrosine hydroxylase mRNA in the substantia nigra but not the ventral tegmental area. After two days of repeated drug injections (twice daily), tyrosine hydroxylase mRNA was decreased in the substantia nigra despite the persistence of an elevated dopamine turnover in the striatum. The decrease in mRNA was still observed after four days of repeated treatment while, at that time, turnover values were not different from control. No changes were observed in the ventral tegmental area. The initial increase in tyrosine hydroxylase mRNA in substantia nigra pars compacta suggests that activation of nigrostriatal neurons triggers a very rapid increase in genomic expression of the enzyme. The following decrease in mRNA levels precedes desensitization to the effects of the drug on dopamine turnover, further illustrating a lack of correspondence between increased neurotransmission and levels of tyrosine hydroxylase mRNA in catecholaminergic neurons of the central nervous system.
Department of Pharmacology, University of Pennsylvania, Philadelphia 19104.
L T
LT
Weiss-Wunder
M F
MF
Chesselet
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004563:Electrochemistry; D005476:Fluphenazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D015347:RNA Probes; D012333:RNA, Messenger / Q000096:biosynthesis*; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis*
D015347:RNA Probes; D012333:RNA, Messenger; D015102:3,4-Dihydroxyphenylacetic Acid; C053619:fluphenazine-N-mustard; D014446:Tyrosine 3-Monooxygenase; D005476:Fluphenazine; D004298:Dopamine