Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.
Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking.
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
Gemma
G
Navarro
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
César
C
Quiroz
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
David
http://orcid.org/0000-0003-0070-2566
D
Moreno-Delgado
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
Adam
A
Sierakowiak
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
Kimberly
K
McDowell
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
Estefanía
E
Moreno
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
William
W
Rea
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224.
Ning-Sheng
NS
Cai
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
David
D
Aguinaga
School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, United Kingdom, and.
Lesley A
LA
Howell
Max Planck Institute of Psychiatry, 80804 Munich, Germany.
Felix
F
Hausch
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
Antonio
A
Cortés
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
Josefa
http://orcid.org/0000-0002-2479-4162
J
Mallol
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
Vicent
V
Casadó
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
Carme
http://orcid.org/0000-0003-2869-6882
C
Lluís
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain.
Enric I
http://orcid.org/0000-0003-4992-7440
EI
Canela
Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, sferre@intra.nida.nih.gov p.mccormick@uea.ac.uk.
Sergi
S
Ferré
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Center for Biomedical Research in Neurodegenerative Diseases Network and Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain, School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, United Kingdom, and sferre@intra.nida.nih.gov p.mccormick@uea.ac.uk.
Peter J
PJ
McCormick
D000818:Animals; D019390:Arrestins / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism; D064446:Orexin Receptors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects*; D000071557:beta-Arrestins; D000099052:CRF Receptor, Type 1
D019390:Arrestins; D018765:Dopamine Uptake Inhibitors; D064446:Orexin Receptors; D018019:Receptors, Corticotropin-Releasing Hormone; D000071557:beta-Arrestins; D000099052:CRF Receptor, Type 1; D000242:Cyclic AMP; D051058:Oncogene Protein v-akt; D003042:Cocaine; D004298:Dopamine
CRF receptor; GPCR heteromer; cocaine; orexin receptor; sigma receptor