Inhibition by miltirone of up-regulation of GABAA receptor alpha4 subunit mRNA by ethanol withdrawal in hippocampal neurons.
Miltirone, a tanshinone isolated from the root of Salvia miltiorrhiza, has been characterized as a low-affinity ligand for central benzodiazepine receptors. We have now shown that this compound bound with low affinity (micromolar range) to central benzodiazepine recognition sites but did not interact with peripheral benzodiazepine receptors. It failed to potentiate Cl(-) currents induced by gamma-aminobutyric acid (GABA) both in Xenopus oocytes expressing recombinant human GABA(A) receptors and in cultured rat hippocampal pyramidal cells, but it inhibited the ability of diazepam to potentiate the effect of GABA in these systems. Miltirone (1-10 microM) also partially inhibited the increase in the abundance of the mRNA for the alpha(4) subunit of the GABA(A) receptor induced by ethanol withdrawal in cultured hippocampal neurons. These results suggest that miltirone might ameliorate the symptoms associated with discontinuation of long-term administration of ethanol or of other positive modulators of the GABA(A) receptor.
Mostallino
Maria Cristina
MC
Section of Neuropsychopharmacology, CNR Institute of Neuroscience, University of Cagliari, Cagliari, Italy. mostall@unica.it
Mascia
Maria Paola
MP
Pisu
Maria Giuseppina
MG
Busonero
Fabio
F
Talani
Giuseppe
G
Biggio
Giovanni
G
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D002540:Cerebral Cortex / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004594:Electrophysiology; D000431:Ethanol / Q000009:adverse effects*; D005445:Flunitrazepam / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010616:Phenanthrenes / Q000494:pharmacology*; D015347:RNA Probes / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D014149:Tranquilizing Agents / Q000494:pharmacology*; D014982:Xenopus laevis
D002492:Central Nervous System Depressants; D018076:DNA, Complementary; D018756:GABA Antagonists; C546260:GABRA4 protein, human; C546262:Gabra4 protein, rat; D007546:Isoquinolines; D010616:Phenanthrenes; D015347:RNA Probes; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014149:Tranquilizing Agents; C068880:miltirone; D000431:Ethanol; D005445:Flunitrazepam; C037850:PK 11195