Orexin-A/Hypocretin-1 Mediates Cocaine-Seeking Behavior in the Posterior Paraventricular Nucleus of the Thalamus via Orexin/Hypocretin Receptor-2

被引:49
作者
Matzeu, Alessandra [1 ]
Kerr, Tony M. [1 ]
Weiss, Friedbert [1 ]
Martin-Fardon, Remi [1 ]
机构
[1] Scripps Res Inst, Mol & Cellular Neurosci Dept, 10550 North Torrey Pines Rd,SP30-2120, La Jolla, CA 92037 USA
基金
美国国家卫生研究院;
关键词
CUE-INDUCED REINSTATEMENT; CORTICOTROPIN-RELEASING-FACTOR; CONTEXT-INDUCED REINSTATEMENT; MIDLINE THALAMUS; REWARD SEEKING; RAT-BRAIN; PAIRED ENVIRONMENT; EXTENDED AMYGDALA; NEURAL ACTIVATION; OREXIN RECEPTORS;
D O I
10.1124/jpet.116.235945
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Orexin/hypocretin (Orx/Hcrt) projections from the lateral hypothalamus to the paraventricular nucleus of the thalamus (PVT) are implicated in drug addiction. Specifically, the posterior section of the PVT (pPVT) innervates brain structures that modulate motivated behavior. This study investigated the role of pPVTOrx/Hcrt transmission in cocaine-seeking behavior. Because the effects of Orx/Hcrt are mediated by two Orx/Hcrt receptors (Hcrt-r1 and Hcrt-r2), we examined the extent to which Hcrt-r1 and Hcrt-r2 are involved in Orx/Hcrt-induced cocaine seeking. Male Wistar rats were made cocaine dependent by self-administering cocaine 6 hours/day (long access) for 21 days. After self-administration training, the rats underwent daily extinction training, during which cocaine was withheld. After extinction, the rats were injected into the pPVT with Orx-A/Hcrt-1 (0-2 mu g) alone or, using a single dose of 0.5 mu g, in combination with an Hcrt-r1 antagonist (SB334867; 0-15 mu g) or an Hcrt-r2 antagonist (TCSOX229; 0-15 mu g). Orx-A/Hcrt-1 alone reinstated (primed) cocaine seeking. Unexpectedly, coadministration of Orx-A/Hcrt-1 with SB334867 did not have any effects on OrxA/Hcrt-1-induced reinstatement, whereas when coadministered with Orx-A/Hcrt-1, TCSOX229 prevented cocaine-seeking behavior. These results indicate that Hcrt-r2 in the pPVT mediates the reinstating effect of Orx-A/Hcrt-1 in animals with a history of cocaine dependence and further identify Hcrt-r2 as a possible molecular target that can guide future therapeutic approaches for the prevention of drug-seeking behavior.
引用
收藏
页码:273 / 279
页数:7
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