Comparative effects of receptor inactivation, 17 beta-estradiol and pertussis toxin on dopaminergic inhibition of prolactin secretion in vitro.
Akin to receptor inactivation with phenoxybenzamine (PBZ) (1 microM, 1 hr), treatment of anterior pituitary cells with 17 beta-estradiol (10 nM, 3 days) right-shifted the dose-response curve for inhibition of prolactin (PRL) secretion by the full agonist R-(-)-N-n-propylnorapomorphine (NPA) and reduced the maximal effect [EC50 (pM) and percent maximal effect: control, 25.4 and 81.2; PBZ, 115.3 and 57.9; 17 beta-estradiol, 358 and 58.6]. PBZ treatment of 17 beta-estradiol-pretreated cultures further reduced the maximal response but did not alter the EC50. Plots of receptor occupancy vs. response indicated a large receptor reserve for NPA (approximately 60%) in control cultures but its abolition by 17 beta-estradiol. 17 beta-Estradiol pretreatment elicited identical rightward shifts (4.5-fold) and similar reductions in maximal PRL inhibition by quinpirole and (+)-3-PPP, although these drugs were partial agonists with dissimilar efficacies relative to NPA (0.61 and 0.12, respectively) at presynaptic striatal D2 receptors. However, receptor inactivation experiments with (+)-3-PPP and quinpirole, and subsequent comparison of receptor occupancy vs. response plots, demonstrated that the relative efficacies of quinpirole and (+)-3-PPP were reversed in the striatum and anterior pituitary. In striatum, half-maximal response to quinpirole and (+)-3-PPP required 6.2 and 30% receptor occupancy, respectively, whereas 25.6 and 9.6% occupancy was required in the pituitary. Pertussis toxin treatment (10 ng/ml, 24 hr) produced large shifts in the dose-response curves for all three agonists (8.4-21.9-fold), but was distinguished from the effects of both PBZ and 17 beta-estradiol by a significant (P < .001) decrease in the slope factor.(ABSTRACT TRUNCATED AT 250 WORDS)
Millhauser Laboratories, Department of Psychiatry, New York University School of Medicine, New York.
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Meller
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Puza
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Diamond
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Lieu
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Bohmaker
D000818:Animals; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D008297:Male; D037342:Pertussis Toxin; D010643:Phenoxybenzamine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects* / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D019257:Quinpirole; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D015259:Dopamine Agents; D004873:Ergolines; D010880:Piperidines; D017448:Receptors, Dopamine D2; D011955:Receptors, Drug; D010566:Virulence Factors, Bordetella; D010643:Phenoxybenzamine; D019257:Quinpirole; D004958:Estradiol; D011388:Prolactin; C026539:preclamol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins