Nociceptin/orphanin FQ modulation of rat midbrain dopamine neurons in primary culture.
Previous microdialysis studies have identified a suppressive effect of the novel opioid peptide nociceptin (also known as orphanin FQ) on dopamine release from mesolimbic neurons. In order to further evaluate the locus of this action, we investigated nociceptin's action in an in vitro model system, namely midbrain dopamine neurons in primary culture. Immunohistochemical analysis revealed abundant tyrosine hydroxylase- and GABA-immunoreactive neurons, with a strong correlation between tyrosine hydroxylase content and basal endogenous dopamine release. Nociceptin (0.01-100 nM) suppressed basal dopamine release by up to 84% (EC50=0.65 nM). This action was reversible by drug removal and attenuated by co-application of the non-peptidergic ORL1 antagonist, Compound B. Nociceptin had no significant effect on dopamine release evoked by direct depolarization of the terminals with elevated extracellular K+, suggesting that nociceptin suppresses dopamine release by modulating the firing rate of the dopamine neurons. Nociceptin also suppressed GABA release from the cultures (45% maximal inhibition; EC50=1.63 nM). Application of the GABA-A antagonist, bicuculline, elevated extracellular dopamine concentrations but the dopamine release inhibiting property of nociceptin persisted in the presence of bicuculline. The NMDA receptor antagonist, D(-)-2-amino-5-phosphononpentanoic acid (AP-5) had no effect on basal dopamine release and failed to modify nociceptin's inhibitory effects. Thus, nociceptin potently modulates dopamine release from midbrain neurons most likely as a result of a direct suppression of dopamine neuronal activity.
Department of Psychiatry, UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759, USA. nmurphy@riken.jp
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Tan
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D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008636:Mesencephalon / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018847:Opioid Peptides / Q000494:pharmacology*; D051381:Rats; D000097629:Nociceptin
D004298:Dopamine; D018847:Opioid Peptides; D000097629:Nociceptin