The neuropeptide nociceptin/orphanin FQ (N/OFQ) system can be activated under conditions of stress and is associated with disorders of emotional regulation and reward processing. N/OFQ and its cognate receptor, NOP, are highly enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and the ventral tegmental area (VTA). We used whole cell electrophysiology in acute rat brain slices to investigate

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... actions of N/OFQ in VTA neurons. Consistent with previous reports, we found that N/OFQ is primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+)) and non-dopaminergic (TH(-)) VTA neurons (effect at 1 μM: 20 ± 4 pA). A smaller population of VTA neurons responded to low dose N/OFQ with small inward currents (effect at 10 nM: -11 ± 2 pA). Application of 100 nM N/OFQ resulted in a markedly diminished response to a second N/OFQ application, consistent with receptor desensitization (14 ± 10% of first response). N/OFQ generated outward currents in VTA neurons that project to the medial prefrontal cortex (mPFC), but inward currents in a subset of VTA neurons that project to posterior anterior cingulate cortex. Interestingly, while N/OFQ inhibited VTA cell bodies that project to the NAc, it had little effect on electrically or optogenetically evoked dopamine released from terminals in the NAc measured ex vivo with fast scan cyclic voltammetry. These results extend our understanding of the N/OFQ system in dopaminergic pathways implicated in many neurobehavioral disorders.