Abstract
In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice. Here, we used behavioral, electrophysiological, and neuroanatomical methods to demonstrate the feasibility of using the novel KORD to study brain circuits involved in motivated behavior in rats. In Exp. 1, we show that SalB dose-dependently decreased spontaneous and cocaine-induced locomotor activity in rats expressing KORD to midbrain (ventral tegmental area/substantia nigra). In Exp. 2, we show that SalB completely inhibited tonic firing in KORD-expressing putative dopamine neurons in midbrain. In Exp. 3, we used a ‘retro-DREADD’ dual-virus approach to restrict expression of KORD in ventral subiculum neurons that project to nucleus accumbens shell. We show that KORD activation selectively decreased novel context-induced Fos expression in this projection. Our results indicate that the novel KORD is a promising tool to selectively inactivate brain areas and neural circuits in rat studies of motivated behavior.
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Acknowledgements
CNO was obtained from the NIH as part of the Rapid Access to Investigative Drug Program funded by the NINDS. NJM, LRW, JMB, BKH, BTH, KK, SW, and YS were supported by NIDA-IRP funds to the laboratories of Yavin Shaham and Bruce Hope. NJM received support from Early Career Fellowship 1053308 by the National Health and Medical Research Council. TEP was supported by NIH grant DA018151. EV is currently employed at Merck. BLR has consulted in the past 18 months with Pfizer, Novartis, Merck and RuiYi Pharmaceuticals. BLR has received an unrestricted grant from Asubio Pharmaceuticals and receives compensation as Deputy Editor of the Journal of Clinical Investigation. BLR has received grant support for DREADD technology unrelated to this manuscript from Merck Pharmacology. BLR was supported by an NIMH BRAIN Initiative Grant.
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Marchant, N., Whitaker, L., Bossert, J. et al. Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats. Neuropsychopharmacol 41, 402–409 (2016). https://doi.org/10.1038/npp.2015.149
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DOI: https://doi.org/10.1038/npp.2015.149
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