Original Article

Neuropsychopharmacology (2016) 41, 402–409; doi:10.1038/npp.2015.149; published online 24 June 2015

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

Nathan J Marchant1,2,7, Leslie R Whitaker1,7, Jennifer M Bossert1,7, Brandon K Harvey3, Bruce T Hope1, Konstantin Kaganovsky1, Sweta Adhikary1, Thomas E Prisinzano4, Eyal Vardy5,6,7, Bryan L Roth6,7 and Yavin Shaham1,7

  1. 1Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA
  2. 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
  3. 3Optogenetics and Transgenic Technology Core, IRP-NIDA, NIH, Bethesda, MD, USA
  4. 4Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, KS, USA
  5. 5Merck Research Laboratories, Kenilworth, NJ, USA
  6. 6Department of Pharmacology, School of Medicine, University of North Carolina Chapel Hill, Chapel Hill, NC, USA

Correspondence: Dr N Marchant or Dr Y Shaham, Behavioral Neuroscience Research Branch, IRP-NIDA, NIH, Bethesda, MD, USA, Tel: +1 443 740 2704, Fax: +1 443 740 2827, E-mail: nathan.marchant@nih.gov or Yshaham@intra.nida.nih.gov

7These authors contributed equally to this work.

Received 23 March 2015; Revised 1 May 2015; Accepted 20 May 2015
Accepted article preview online 28 May 2015; Advance online publication 24 June 2015

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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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