Nicotine self-administration in the rat: effects of hypocretin antagonists and changes in hypocretin mRNA.
BACKGROUND
The hypocretin (hcrt) system has been implicated in addiction-relevant effects of several drugs, but its role in nicotine dependence has been little studied.


OBJECTIVE
These experiments examined the role of the hcrt system in nicotine reinforcement.


METHODS
Rats were trained for nicotine self-administration (NSA) on fixed-ratio schedules. The effects of acute, presession treatments with the hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant were examined on NSA maintained on a fixed-ratio (FR) 5 schedule. Gene expression for the hcrt system (mRNA for hcrt, hcrtR1, and hcrtR2) was measured in animals following NSA on a FR 1 schedule for a 19-day period.


RESULTS
The hcrtR1 antagonist SB334867 and the hcrtR1/2 antagonist almorexant both reduced NSA dose-dependently (significantly at doses of 30 and 300 mg/kg, respectively); SB334867 did not affect food-maintained responding whereas almorexant (at the 300 mg/kg) did. Tissue from animals collected 5 h after self-administration showed an increase in hcrtR1 mRNA in the arcuate nucleus compared to control subjects. In tissue collected immediately after a similar 19-day self-administration period, mRNA for hcrtR1 was decreased in the rostral lateral hypothalamus compared to controls.


CONCLUSIONS
These data confirm a previous report (Hollander et al., Proc Natl Acad Sci U S A 105:19480-19485, 2008) that the hypocretin receptor hcrtR1 is activated in nicotine reinforcement and in addition show that both the arcuate nucleus and lateral hypothalamus are sites at which hcrt receptor mechanisms may influence reinforcement. Different patterns of mRNA expression at different times after NSA suggest that changes in the hcrt system may be labile with time.
LeSage
Mark G
MG
Minneapolis Medical Research Foundation, 914 S 8th Street, Minneapolis, MN 55404, USA.
Perry
Jennifer L
JL
Kotz
Catherine M
CM
Shelley
David
D
Corrigall
William A
WA
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D001583:Benzoxazoles / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007262:Infusions, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009287:Naphthyridines; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D064446:Orexin Receptors; D000068797:Orexins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D000081:Acetamides; D001583:Benzoxazoles; C578625:Hcrtr2 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D009287:Naphthyridines; D009479:Neuropeptides; D018722:Nicotinic Agonists; D064446:Orexin Receptors; D000068797:Orexins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D009538:Nicotine; D014508:Urea; C519150:almorexant