Differential Modulation of Ventral Tegmental Area Circuits by the Nociceptin/Orphanin FQ System

Abstract

The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and ventral tegmental area (VTA). We used whole-cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+))) and non-dopaminergic (TH(–)) VTA neurons; effect at 1 μ m : 20 ± 4 pA. Surprisingly, this effect was mediated by augmentation of postsynaptic GABA A R currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ-induced outward currents were K + channel dependent. A smaller population, 17% of all VTA neurons, responded to low concentrations of N/OFQ with inward currents (10 n m : −11 ± 2 pA). Following 100 n m N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 ± 10% of first response) but not in SNc neurons (90 ± 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex (pACC)-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured ex vivo with fast scan cyclic voltammetry (FSCV). These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders.

Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders

“…These effects are mediated by NOP receptors and appear to depend on enhancement of potassium conductance [ 66 , 67 ]. This conventional mechanism of action has been recently questioned in a study proposing the possibility that N/OFQ may attenuated DA transmission through indirect mechanisms involving presynaptic GABA transmission [ 68 ]. However, more conclusive experiments are needed to support this alternative hypothesis.…”

“…At this level, N/OFQ treatment produced a decrease in tyrosine hydroxylase (TH) phosphorylation, DA synthesis and postsynaptic DA receptor D1 signaling [ 69 ]. On the other hand, in vivo microdialysis and ex vivo fast scan cyclic voltammetry studies revealed that N/OFQ application within the NAc has little or no basal effects on DA accumulation and release [ 68 , 70 ]. Altogether these data point to a predominant role of the VTA in mediating the effects of N/OFQ in DA release.…”

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

“…Wash in of JNJ-67953964 seemed to generate an inward current in a subset of neurons, and surprisingly this was observed more often at 10 nM than at 100 nM. We previously found that a small subset of VTA neurons respond to nociceptin/orphanin FQ with an inward current only at low concentrations, peaking at 10 nM [44], and CRF also increases VTA glutamatergic EPSCs at lower concentrations and inhibits them at higher concentrations [45], making such a pattern not entirely unprecedented. Together, these observations indicate potentially important, unanticipated properties of JNJ-67953964.…”

Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport

“…With regard to the cellular actions mediated by NOP activation by nociceptin/orphanin N/OFQ, they resemble those mediated by the other classes of opioid receptors, particularly the activation of K + conductances, the inhibition of high threshold voltage-gated Ca 2+ channels and the inhibition of transmitter release [121]. While most of VTA neurons responded with large outward currents to NOP activation [116], a recent study found that, NOP effects on the intrinsic membrane currents have different features depending on the projection areas of VTA and SNpc DA neuronal populations [117]. Medial-PFC and NAcc-projecting VTA neurons respond to NOP activation with an outward (inhibitory) membrane current; posterior anterior cingulate cortex (pACC)-projecting VTA neurons responded to NOP activation with an inward (excitatory) membrane current [117].…”