Hypocretins regulate the anxiogenic-like effects of nicotine and induce reinstatement of nicotine-seeking behavior.
Emerging evidence suggests that the hypocretinergic system is involved in addictive behavior. In this study, we investigated the role of these hypothalamic neuropeptides in anxiety-like responses of nicotine and stress-induced reinstatement of nicotine-seeking behavior. Acute nicotine (0.8 mg/kg, s.c.) induced anxiogenic-like effects in the elevated plus-maze and activated the paraventricular nucleus of the hypothalamus (PVN) as revealed by c-Fos expression. Pretreatment with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 or preprohypocretin gene deletion blocked both nicotine effects. In the PVN, SB334867 also prevented the activation of corticotrophin releasing factor (CRF) and arginine-vasopressin (AVP) neurons, which expressed Hcrtr-1. In addition, an increase of the percentage of c-Fos-positive hypocretin cells in the perifornical and dorsomedial hypothalamic (PFA/DMH) areas was found after nicotine (0.8 mg/kg, s.c.) administration. Intracerebroventricular infusion of hypocretin-1 (Hcrt-1) (0.75 nmol/1 mul) or footshock stress reinstated a previously extinguished nicotine-seeking behavior. The effects of Hcrt-1 were blocked by SB334867, but not by the CRF1 receptor antagonist antalarmin. Moreover, SB334867 did not block CRF-dependent footshock-induced reinstatement of nicotine-seeking while antalarmin was effective in preventing this nicotine motivational response. Therefore, the Hcrt system interacts with CRF and AVP neurons in the PVN and modulates the anxiogenic-like effects of nicotine whereas Hcrt and CRF play a different role in the reinstatement of nicotine-seeking. Indeed, Hcrt-1 reinstates nicotine-seeking through a mechanism independent of CRF activation whereas CRF mediates the reinstatement induced by stress.
Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Pompeu Fabra University, 08003 Barcelona, Spain.
Ainhoa
A
Plaza-Zabala
Elena
E
Martín-García
Luis
L
de Lecea
Rafael
R
Maldonado
Fernando
F
Berrendero
D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*; D001127:Arginine Vasopressin / Q000378:metabolism; D016739:Behavior, Addictive / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*; D001583:Benzoxazoles / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005108:Extinction, Psychological; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009287:Naphthyridines; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D009538:Nicotine / Q000008:administration & dosage / Q000494:pharmacology*; D064446:Orexin Receptors; D000068797:Orexins; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C103016:antalarmin; D001127:Arginine Vasopressin; D000099052:CRF Receptor, Type 1; D009538:Nicotine; D014508:Urea; D003346:Corticotropin-Releasing Hormone