TY - JOUR
T1 - A role for hypocretin/orexin receptor-1 in cue-induced reinstatement of nicotine-seeking behavior
AU - Plaza-Zabala, Ainhoa
AU - Flores, África
AU - Martín-García, Elena
AU - Saravia, Rocío
AU - Maldonado, Rafael
AU - Berrendero, Fernando
N1 - Funding Information:
This work was supported by the Instituto de Salud Carlos III grants, no. PI07/0559, no. PI10/00316, and no. RD06/001/001 (RTA-RETICS), by the Spanish Ministry of Science and Technology, Consolider-C no. SAF2007-64062 and no. SAF2011-29864, the Catalan Government (SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies (ICREA Academia program). AP-Z and ÁF are recipients of a predoctoral fellowship from the Spanish Ministry of Education. We thank Cristina Fernández and Marta Linares for invaluable technical assistance.
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - cue
KW - glutamate
KW - hypocretin
KW - nicotine
KW - PKC
KW - reinstatement
UR - http://www.scopus.com/inward/record.url?scp=84880327141&partnerID=8YFLogxK
U2 - 10.1038/npp.2013.72
DO - 10.1038/npp.2013.72
M3 - Article
C2 - 23518606
AN - SCOPUS:84880327141
SN - 0893-133X
VL - 38
SP - 1724
EP - 1736
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 9
ER -