kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists.
Kappa-opioid receptor agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine receptor systems involved in drug reinforcement. kappa-Opioid receptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid receptor agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine receptor system in vivo in primates. The effectiveness of dopamine D(2)-like receptor agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid receptor agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid receptor agonists to modulate dopamine D(2)-like receptor function, and may also be used to quantify dopamine D(2)-like receptor agonist potency in primates.
Butelman
E R
ER
Laboratory on the Biology of Addictive Diseases, The Rockefeller University (Box 171), 1230 York Avenue, New York, NY 10021, USA. butelme@mail.rockefeller.edu
Kreek
M J
MJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D044482:Benzeneacetamides; D016292:Procedural Sedation; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008297:Male; D011388:Prolactin / Q000097:blood / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D001552:Benzazepines; D044482:Benzeneacetamides; D018491:Dopamine Agonists; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D017473:Receptors, Opioid, kappa; D013764:Tetrahydronaphthalenes; D019257:Quinpirole; C071262:SK&F 82958; D011388:Prolactin; C045444:U 69593; C031349:7-hydroxy-2-N,N-dipropylaminotetralin