Increase of tyrosine hydroxylase and its mRNA in the rat substantia nigra pars reticulata by diazepam and picrotoxin.
An involvement of GABAA receptors in the regulation of tyrosine hydroxylase (TH) gene expression in the substantia nigra pars reticulata (SNr) was investigated using immunohistochemistry (IMHC) and nonradioactive in situ hybridization histochemistry (ISH). The number of TH-positive cells was increased for both ISH and IMHC 8 h after a single administration of benzodiazepine diazepam, which facilitates GABAA-receptor-mediated transmission and reduces dopamine release in the substantia nigra (SN). Such increase in TH staining was suppressed when a dopamine D2 receptor agonist quinpirole was administered 10 min after diazepam. Co-administration of diazepam with a dopamine antagonist haloperidol did not further elevate, but rather, reduced haloperidol-induced increases in TH labeling. These results suggest that haloperidol and diazepam regulate TH gene expression in the SNr commonly by depressing dopaminergic transmission, and that diazepam activates TH expression in a group of SNr neurons which express this gene after haloperidol treatment. Moreover, a GABAA receptor antagonist, picrotoxin, activated TH gene expression in the SNr, and diazepam antagonized picrotoxin effects. Since picrotoxin increases neuronal activity, additional mechanisms will operate on TH gene expression. In conclusion, GABAergic substances will activate TH gene expression in SNr neurons (1) through decreasing spontaneous somato-dendritic dopamine release in the substantia nigra and/or (2) by increasing the activity of these neurons.
Stork
O
O
Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki, Japan.
Hashimoto
T
T
Obata
K
K
D000818:Animals; D003975:Diazepam / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology; D004873:Ergolines / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D010852:Picrotoxin / Q000494:pharmacology*; D019257:Quinpirole; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism*
D003975:Diazepam; D015259:Dopamine Agents; D004873:Ergolines; D006220:Haloperidol; D010852:Picrotoxin; D019257:Quinpirole; D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase