Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine.

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Navarro G, Moreno E, Aymerich M, Marcellino D, McCormick PJ, Mallol J, Cortes A, Casado V, Canela EI, Ortiz J, Fuxe K, Lluis C, Ferre S, Franco R

Direct involvement of sigma-1 receptors in the dopamine D1 receptor-mediated effects of cocaine.

Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18676-81. doi: 10.1073/pnas.1008911107. Epub 2010 Oct 18.

PubMed ID

20956312 [ View in PubMed

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Abstract

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 sigma-1 receptors, the physiological role of which is largely unknown. In the present study, D(1)R and sigma(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 sigma(1)R-dependent manner. Some of these effects were also demonstrated in murine striatal slices and were absent in sigma(1)R KO mice, providing evidence for the existence of sigma(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 sigma(1)R-D(1)R heteromerization, and provide a unique perspective toward understanding the molecular basis of cocaine addiction.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cocaine	Sigma non-opioid intracellular receptor 1	Protein	Humans	Unknown	Agonist	Details