Orexin-Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

被引：53

作者：

Navarro, Gemma ^{[1
,2
]}

Quiroz, Cesar ^{[3
]}

Moreno-Delgado, David ^{[1
,2
]}

Sierakowiak, Adam ^{[3
]}

McDowell, Kimberly ^{[3
]}

Moreno, Estefania ^{[1
,2
]}

Rea, William ^{[3
]}

Cai, Ning-Sheng ^{[3
]}

Aguinaga, David ^{[1
,2
]}

Howell, Lesley A. ^{[4
]}

Hausch, Felix ^{[5
]}

Cortes, Antonio ^{[1
,2
]}

Mallol, Josefa ^{[1
,2
]}

Casado, Vicent ^{[1
,2
]}

Lluis, Carme ^{[1
,2
]}

Canela, Enric I. ^{[1
,2
]}

Ferre, Sergi ^{[3
]}

McCormick, Peter J. ^{[1
,2
,4
]}

机构：

[1] Univ Barcelona, Fac Biol, Ctr Biomed Res Neurodegenerat Dis Network, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain

[2] Univ Barcelona, Inst Biomed, E-08028 Barcelona, Spain

[3] Natl Inst Drug Abuse, Integrat Neurobiol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA

[4] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk, England

[5] Max Planck Inst Psychiat, D-80804 Munich, Germany

来源：

JOURNAL OF NEUROSCIENCE | 2015年 / 35卷 / 17期

关键词：

cocaine; CRF receptor; GPCR heteromer; orexin receptor; sigma receptor; STRESS-INDUCED RELAPSE; PROTEIN-COUPLED RECEPTORS; CRF-BINDING-PROTEIN; SIGMA-1; RECEPTORS; DOPAMINE NEURONS; INDUCED REINSTATEMENT; DRUG SEEKING; OREXIN/HYPOCRETIN; HYPOTHALAMUS; PHARMACOLOGY;

D O I：

10.1523/JNEUROSCI.4364-14.2015

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 sigma(1) receptor (sigma R-1) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the sigma R-1-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.

引用

页码：6639 / 6653

页数：15

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