Highlights d pnVTA Pnoc neurons project locally onto VTA dopamine neurons d pnVTA Pnoc neurons become active when animals are demotivated to seek rewards d Stimulation of pnVTA Pnoc neurons reduces breakpoint and promotes avoidance behavior d VTA dopamine neuron NOPR expression is necessary to limit reward-seeking behavior Authors

Optogenetics has revolutionized neuroscience by providing means to control cell signaling with spatiotemporal control in discrete cell types. In this review, we summarize four major classes of optical tools to manipulate neuromodulatory GPCR signaling: opsins (including engineered chimeric receptors); photoactivatable proteins; photopharmacology through caging - photoswitchable molecules; fluorescent protein based reporters and biosensors. Additionally, we highlight technologies to utilize these tools in vitro and in vivo, including Cre dependent viral vector expression and two-photon microscopy. These emerging techniques targeting specific members of the GPCR signaling pathway offer an expansive base for investigating GPCR signaling in behavior and disease states, in addition to paving a path to potential therapeutic developments.

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Comprehensive studies that consolidate selective ligands, quantitative comparisons of G protein versus arrestin-2/3 coupling, together with structure-activity relationship models for G protein-coupled receptor (GPCR) systems are less commonly employed. Here we examine biased signaling at the nociceptin/orphanin FQ opioid receptor (NOPR), the most recently identified member of the opioid receptor family.