Format

Send to

Choose Destination
Neuropsychopharmacology. 2016 Jan;41(2):402-9. doi: 10.1038/npp.2015.149. Epub 2015 May 28.

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

Author information

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

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.

PMID:
26019014
PMCID:
PMC5130116
DOI:
10.1038/npp.2015.149
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center