Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzoxazoles / pharmacology
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Conditioning, Operant / drug effects
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Conditioning, Operant / physiology*
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Cues
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Drug-Seeking Behavior / drug effects
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Drug-Seeking Behavior / physiology*
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Extinction, Psychological / drug effects
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Extinction, Psychological / physiology
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Hypothalamus / drug effects
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Hypothalamus / physiology
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Isoquinolines / pharmacology
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Male
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Mice
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Microinjections
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Naphthyridines
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Nerve Tissue Proteins / metabolism
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Neurons / drug effects
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Neurons / physiology
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Nicotine / administration & dosage
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Nicotine / pharmacology*
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Nicotinic Agonists / administration & dosage
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Nicotinic Agonists / pharmacology*
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Nucleus Accumbens / metabolism
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Orexin Receptor Antagonists
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Orexin Receptors / physiology*
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Phosphorylation
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Piperidines / administration & dosage
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Piperidines / pharmacology
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Prefrontal Cortex / metabolism
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Protein Kinase Inhibitors / pharmacology
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Pyridines / pharmacology
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Receptors, AMPA / metabolism
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Receptors, N-Methyl-D-Aspartate / metabolism
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Self Administration
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Urea / analogs & derivatives
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Urea / pharmacology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
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1-(3,4-dihydro-6,7-dimethoxy-2(1H)-isoquinolinyl)-3,3-dimethyl-2-((4-pyridinylmethyl)amino)-1-butanone
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Benzoxazoles
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Gprin1 protein, mouse
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Hcrtr1 protein, mouse
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Hcrtr2 protein, mouse
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Isoquinolines
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Naphthyridines
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Nerve Tissue Proteins
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Nicotinic Agonists
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Orexin Receptor Antagonists
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Orexin Receptors
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Piperidines
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Protein Kinase Inhibitors
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Pyridines
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Receptors, AMPA
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Receptors, N-Methyl-D-Aspartate
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NPC 15437
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Nicotine
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Urea
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p38 Mitogen-Activated Protein Kinases
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glutamate receptor ionotropic, AMPA 2