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Neuron. 2015 May 20;86(4):936-946. doi: 10.1016/j.neuron.2015.03.065. Epub 2015 Apr 30.

A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior.

Author information

1
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
2
Neurology Department, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
3
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; National Institute of Drug Abuse, Baltimore, MD 21224, USA.
4
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
5
Neurology Department, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
6
Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
7
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
8
Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298, USA.
9
Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; National Institute of Drug Abuse, Baltimore, MD 21224, USA. Electronic address: michael.krashes@nih.gov.
10
Department of Pharmacology and National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. Electronic address: bryan_roth@med.unc.edu.

Abstract

DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.

PMID:
25937170
PMCID:
PMC4441592
DOI:
10.1016/j.neuron.2015.03.065
[Indexed for MEDLINE]
Free PMC Article

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