Chronic exposure to anxiolytic drugs, working by different mechanisms causes up-regulation of dihydropyridine binding sites on cultured bovine adrenal chromaffin cells.
Exposure of bovine adrenal chromaffin cells to ethanol [50 mM], alprazolam [10(-7) M] and buspirone [10(-7) M] inhibited basal and carbachol-induced release of catecholamines from these cells. The inhibition produced by alprazolam was prevented, and that produced by ethanol inhibited, by the presence of the benzodiazepine receptor antagonist, flumazenil [10(-8) M]. The inhibition produced by buspirone was unaffected by flumazenil, but was mimicked by the selective 5-HT1A receptor agonist, 8-OH DPAT and prevented by the 5-HT receptor antagonist spiperone [10(-6) M]. These results suggest that bovine adrenal chromaffin cells express GABAA receptors, containing a benzodiazepine recognition site and also 5-HT1A receptors. Ethanol and alprazolam appear to inhibit the excitability of bovine adrenal chromaffin cells by an action related to the former, while buspirone probably inhibits these cells through the latter. Maintaining bovine adrenal chromaffin cells for several days in culture medium, containing inhibitory concentrations of ethanol alprazolam or buspirone, produced a marked increase in binding sites for a [3H]dihydropyridine [DHP] calcium channel antagonist, on cell membranes. The increase in binding sites produced by alprazolam was greater than that produced by the other two agents and was almost completely prevented by the concomitant presence of flumazenil. The effects of ethanol and buspirone on the binding of DHP were not prevented by flumazenil. The results suggest that drugs which decrease excitability of bovine adrenal chromaffin cells by different mechanisms, may evoke a similar adaptive response involving an increase in DHP-sensitive calcium channels.
Division of Biomedical Sciences, King's College, London, U.K.
C H
CH
Brennan
J M
JM
Littleton
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism*; D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D002065:Buspirone / Q000494:pharmacology; D015220:Calcium Channels; D002217:Carbachol / Q000494:pharmacology; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D002838:Chromaffin System / Q000187:drug effects / Q000378:metabolism*; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D066298:In Vitro Techniques; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D015220:Calcium Channels; D002395:Catecholamines; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D013764:Tetrahydronaphthalenes; D000431:Ethanol; D005442:Flumazenil; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D002217:Carbachol; D002065:Buspirone; D000525:Alprazolam