title: Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats.
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.
authors.affiliation: Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA.|Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Marchant
authors.affiliation: Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA.
authors.forename: Leslie R
authors.initials: LR
authors.lastname: Whitaker
authors.affiliation: Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Bossert
authors.affiliation: Optogenetics and Transgenic Technology Core, IRP-NIDA, NIH, Bethesda, MD, USA.
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.affiliation: Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Hope
authors.affiliation: Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA.
authors.forename: Konstantin
authors.identifier: http://orcid.org/0000-0002-1577-109X
authors.initials: K
authors.lastname: Kaganovsky
authors.affiliation: Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA.
authors.forename: Sweta
authors.initials: S
authors.lastname: Adhikary
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.affiliation: Merck Research Laboratories, Kenilworth, NJ, USA.|Department of Pharmacology, School of Medicine, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA.
authors.forename: Yavin
authors.initials: Y
authors.lastname: Shaham
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics; D004224:Diterpenes / Q000494:pharmacology; D045785:Diterpenes, Clerodane; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D005822:Genetic Vectors; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000378:metabolism*
chemical_list: D002491:Central Nervous System Agents; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D018765:Dopamine Uptake Inhibitors; D017473:Receptors, Opioid, kappa; C508456:salvinorin B; D003042:Cocaine