kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D-2-like receptor agonists

Kappa (kappa)-opioid receptor agonists may have pharmacotherapeutic potenti al in the management of psychostimulant abuse, due to their ability to modu late dopamine receptor systems involved in drug reinforcement, K-Opioid rec eptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior p ituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa -opioid receptor agonists (e.g., (+)-(5 alpha ,7 alph a ,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1 -oxaspiro[4.5]dec-8-yl]-benzcne acetamide (U69,593)) to modulate a dopamine receptor system in vivo in prim ates. 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 prolacti n release (ID50 values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D-2-receptor agonist (+/-)-6-chloro-7,8-dihydeoxy-3-allyl-1-pheny l-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, t he 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 prominen t effect of centrally penetrating K-opioid receptor agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), c onsistent with K-opioid receptor mediation of this effect. These studies su ggest that prolactin release is a valid biomarker for the ability of K-opio id receptor agonists to modulate dopamine D-2-like receptor function, and m ay also be used to quantify dopamine D-2-like receptor agonist potency in p rimate. (C) 2001 Published by Elsevier Science B.V.