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.
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.
Gemma
G
Navarro
Estefanía
E
Moreno
Marisol
M
Aymerich
Daniel
D
Marcellino
Peter J
PJ
McCormick
Josefa
J
Mallol
Antoni
A
Cortés
Vicent
V
Casadó
Enric I
EI
Canela
Jordi
J
Ortiz
Kjell
K
Fuxe
Carmen
C
Lluís
Sergi
S
Ferré
Rafael
R
Franco
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