title: Insular hypocretin transmission regulates nicotine reward.
abstract: Damage to the insular cortex can profoundly disrupt tobacco addiction in human smokers, reflected in spontaneous cessation of the tobacco habit and persistently decreased urge to smoke. Little is known concerning the neurobiological mechanisms through which the insula may control the maintenance of the tobacco habit. Emerging evidence suggests that hypocretin (orexin) transmission may play an important role in drug reinforcement processes, but its role in the rewarding actions of nicotine, considered the key addictive component of tobacco smoke, remains largely unexplored. Here we show that blockade of hypocretin transmission at hypocretin-1 (Hcrt-1; orexin-1) receptors decreases i.v. nicotine self-administration in rats and the motivation to obtain the drug. Blockade of Hcrt-1 receptors also abolished the stimulatory effects of nicotine on brain reward circuitries, as measured by reversal of nicotine-induced lowering of intracranial self-stimulation thresholds. In addition, we show that hypocretin-containing fibers innervate the insula, Hcrt-1 receptors are located on insular cells, and blockade of Hcrt-1 receptors in the insula but not in the adjacent somatosensory cortex decreases nicotine self-administration. These data demonstrate that insular hypocretin transmission plays a permissive role in the motivational properties of nicotine, and therefore may be a key neurobiological substrate necessary for maintaining tobacco addiction in human smokers.
authors.affiliation: Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hollander
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cameron
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kenny
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000493:pharmacokinetics; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009042:Motivation; D009287:Naphthyridines; D009479:Neuropeptides / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D012201:Reward; D012646:Self Administration; D012907:Smoking / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D014029:Tobacco Use Disorder / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives / Q000493:pharmacokinetics
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D018722:Nicotinic Agonists; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D009538:Nicotine; D014508:Urea