title: Cocaine disrupts histamine H3 receptor modulation of dopamine D1 receptor signaling: σ1-D1-H3 receptor complexes as key targets for reducing cocaine's effects.
abstract: The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H3 receptor-mediated inhibition of D1 receptor function. This blockade requires the σ1 receptor and occurs upon cocaine binding to σ1-D1-H3 receptor complexes. The cocaine-mediated disruption leaves an uninhibited D1 receptor that activates Gs, freely recruits β-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of σ1 receptor, we show that blockade of σ1 receptor by an antagonist restores the protective H3 receptor-mediated brake on D1 receptor signaling and prevents the cell death from elevated D1 receptor signaling. These findings suggest that a combination therapy of σ1R antagonists with H3 receptor agonists could serve to reduce some effects of cocaine.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute of Biomedicine of the University of Barcelona (IBUB) and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, 08028 Spain, Neuroscience Institute and Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitat Autónoma de Barcelona, 08193 Bellaterra, Spain, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, United Kingdom NR4 7TJ.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Moreno
authors.forename: David
authors.initials: D
authors.lastname: Moreno-Delgado
authors.forename: Gemma
authors.initials: G
authors.lastname: Navarro
authors.forename: Hanne M
authors.initials: HM
authors.lastname: Hoffmann
authors.forename: Silvia
authors.initials: S
authors.lastname: Fuentes
authors.forename: Santi
authors.initials: S
authors.lastname: Rosell-Vilar
authors.forename: Paola
authors.initials: P
authors.lastname: Gasperini
authors.forename: Mar
authors.initials: M
authors.lastname: Rodríguez-Ruiz
authors.forename: Mireia
authors.initials: M
authors.lastname: Medrano
authors.forename: Josefa
authors.initials: J
authors.lastname: Mallol
authors.forename: Antoni
authors.initials: A
authors.lastname: Cortés
authors.forename: Vicent
authors.initials: V
authors.lastname: Casadó
authors.forename: Carme
authors.initials: C
authors.lastname: Lluís
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
authors.forename: Jordi
authors.initials: J
authors.lastname: Ortiz
authors.forename: Enric
authors.initials: E
authors.lastname: Canela
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D001552:Benzazepines / Q000008:administration & dosage / Q000378:metabolism; D045744:Cell Line, Tumor; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000097605:Sigma-1 Receptor
chemical_list: D001549:Benzamides; D001552:Benzazepines; D003042:Cocaine; D017447:Receptors, Dopamine D1; D018100:Receptors, Histamine H3; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C534628:SCH 23390; C030265:nemonapride