Kappa opioid receptor-mediated regulation of dopaminergic neurons in the rat brain.
The effect of the kappa opioid receptor agonist U-50,488 [trans-3,4-dichloro-N-methyl-N-[2-pyrrolindinyl)-cyclohexyl]-benze ne- acetamide] was examined on the activity of dopamine (DA) neurons comprising the nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophysial systems in the male rat brain under basal and stimulated conditions. DA neuronal activity was estimated by measuring: 1) the accumulation of 3,4-dihydroxyphenylalanine after administration of a decarboxylase inhibitor and 2) the concentration of the DA metabolite 3,4-dihydroxyphenyla-cetic acid in brain (striatum, nucleus accumbens and median eminence) and pituitary regions (intermediate lobe and neural lobe) containing terminals of these neurons. Under basal (non-stimulated) conditions, U-50,488 produced a dose- and time-related decrease in the activity of tuberohypophysial DA neurons, but failed to alter the activity of nigrostriatal, mesolimbic or tuberoinfundibular DA neurons. The ability of U-50,488 to inhibit the basal activity of tuberohypophysial DA neurons was blocked by pretreatment with the kappa opioid antagonist nor-binaltorphimine. The activity of nigrostriatal, mesolimbic and intermediate lobe tuberohypophysial DA neurons was increased by haloperidol, whereas the activity of tuberoinfundibular DA neurons was increased by prolactin. U-50,488 decreased the activity of nigrostriatal, mesolimbic and tuberohypophysial DA neurons in haloperidol-treated rats, and decreased the activity of tuberoinfundibular DA neurons in prolactin-treated rats. These results indicate that activation of kappa opioid receptors inhibits all DA neuronal systems in the brain, but that this effect on nigrostriatal, mesolimbic and tuberoinfundibular DA neurons is evident only after these neurons have been activated.
Manzanares
J
J
Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
Lookingland
K J
KJ
Moore
K E
KE
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D017473:Receptors, Opioid, kappa
D000700:Analgesics; D011759:Pyrrolidines; D011954:Receptors, Dopamine; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D015102:3,4-Dihydroxyphenylacetic Acid; D004295:Dihydroxyphenylalanine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer