A New DREADD Facilitates the Multiplexed Chemogenetic Interrogation of Behavior.
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.
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.
Eyal
E
Vardy
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.
J Elliott
JE
Robinson
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.
Chia
C
Li
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.
Reid H J
RHJ
Olsen
Neurology Department, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
Jeffrey F
JF
DiBerto
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.
Patrick M
PM
Giguere
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.
Flori M
FM
Sassano
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.
Xi-Ping
XP
Huang
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.
Hu
H
Zhu
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.
Daniel J
DJ
Urban
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.
Kate L
KL
White
Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Joseph E
JE
Rittiner
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.
Nicole A
NA
Crowley
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.
Kristen E
KE
Pleil
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.
Christopher M
CM
Mazzone
Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298, USA.
Philip D
PD
Mosier
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.
Juan
J
Song
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.
Thomas L
TL
Kash
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.
C J
CJ
Malanga
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.
Michael J
MJ
Krashes
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.
Bryan L
BL
Roth
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D008024:Ligands; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D004224:Diterpenes; D045785:Diterpenes, Clerodane; D008024:Ligands; D017473:Receptors, Opioid, kappa; C508456:salvinorin B