期刊
NEUROPSYCHOPHARMACOLOGY
卷 38, 期 9, 页码 1724-1736出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2013.72
关键词
nicotine; hypocretin; cue; reinstatement; glutamate; PKC
资金
- Instituto de Salud Carlos III grants [PI07/0559, PI10/00316, RD06/001/001]
- Spanish Ministry of Science and Technology, Consolider-C [SAF2007-64062, SAF2011-29864]
- Catalan Government [SGR2009-00731]
- Catalan Institution for Research and Advanced Studies (ICREA Academia program)
- Spanish Ministry of Education
Hypocretin/orexin signaling is critically involved in relapse to drug-seeking behaviors. In this study, we investigated the involvement of the hypocretin system in the reinstatement of nicotine-seeking behavior induced by nicotine-associated cues. Pretreatment with the hypocretin receptor-1 antagonist SB334867, but not with the hypocretin receptor-2 antagonist TCSOX229, attenuated cue-induced reinstatement of nicotine-seeking, which was associated with an activation of hypocretin neurons of the lateral and perifornical hypothalamic areas. In addition, relapse to nicotine-seeking increased the phosphorylation levels of GluR2-Ser880, NR1-Ser890, and p38 MAPK in the nucleus accumbens (NAc), but not in the prefrontal cortex. Notably, phosphorylation levels of NR1-Ser890 and p38 MAPK, but not GluR2-Ser880, were dependent on hypocretin receptor-1 activation. The intra-accumbens infusion of the protein kinase C (PKC) inhibitor NPC-15437 reduced nicotine-seeking behavior elicited by drug-paired cues consistent with the PKC-dependent phosphorylations of GluR2-Ser880 and NR1-Ser890. SB334867 failed to modify cue-induced reinstatement of food-seeking, which did not produce any biochemical changes in the NAc. These data identify hypocretin receptor-1 and PKC signaling as potential targets for the treatment of relapse to nicotine-seeking induced by nicotine-associated cues.
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