Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine.
It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D(1) receptors (D(1)Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, the physiological role of which is largely unknown. In the present study, D(1)R and σ(1)R were found to heteromerize in transfected cells, where cocaine robustly potentiated D(1)R-mediated adenylyl cyclase activation, induced MAPK activation per se and counteracted MAPK activation induced by D(1)R stimulation in a dopamine transporter-independent and σ(1)R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in σ(1)R KO mice, providing evidence for the existence of σ(1)R-D(1)R heteromers in the brain. Therefore, these results provide a molecular explanation for which D(1)R plays a more significant role in the behavioral effects of cocaine, through σ(1)R-D(1)R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.
Navarro
Gemma
G
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, and Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
Moreno
Estefanía
E
Aymerich
Marisol
M
Marcellino
Daniel
D
McCormick
Peter J
PJ
Mallol
Josefa
J
Cortés
Antoni
A
Casadó
Vicent
V
Canela
Enric I
EI
Ortiz
Jordi
J
Fuxe
Kjell
K
Lluís
Carmen
C
Ferré
Sergi
S
Franco
Rafael
R
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002460:Cell Line; D003042:Cocaine / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000209:etiology / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020836:Protein Structure, Quaternary / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D017480:Receptors, sigma / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000097605:Sigma-1 Receptor
D003042:Cocaine; D017447:Receptors, Dopamine D1; D017480:Receptors, sigma; D011994:Recombinant Proteins; D000097605:Sigma-1 Receptor