Dataset Information

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.

SUBMITTER: Hollander JA

PROVIDER: S-EPMC2614786 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Insular hypocretin transmission regulates nicotine reward.

Hollander Jonathan A JA Lu Qun Q Cameron Michael D MD Kamenecka Theodore M TM Kenny Paul J PJ

Proceedings of the National Academy of Sciences of the United States of America 20081124 49

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, consi ...[more]

PMID: 19033203

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Project description:The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression.We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals.Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy.

Project description:Background and hypothesisRisk-taking in specific contexts can be beneficial, leading to rewarding outcomes. Schizophrenia is associated with disadvantageous decision-making, as subjects pursue uncertain risky rewards less than controls. However, it is unclear whether this behavior is associated with more risk sensitivity or less reward incentivization. Matching on demographics and intelligence quotient (IQ), we determined whether risk-taking was more associated with brain activation in regions affiliated with risk evaluation or reward processing.Study designSubjects (30 schizophrenia/schizoaffective disorder, 30 controls) completed a modified, fMRI Balloon Analogue Risk Task. Brain activation was modeled during decisions to pursue risky rewards and parametrically modeled according to risk level.Study resultsThe schizophrenia group exhibited less risky-reward pursuit despite previous adverse outcomes (Average Explosions; F(1,59) = 4.06, P = .048) but the comparable point at which risk-taking was volitionally discontinued (Adjusted Pumps; F(1,59) = 2.65, P = .11). Less activation was found in schizophrenia via whole brain and region of interest (ROI) analyses in the right (F(1,59) = 14.91, P < 0.001) and left (F(1,59) = 16.34, P < 0.001) nucleus accumbens (NAcc) during decisions to pursue rewards relative to riskiness. Risk-taking correlated with IQ in schizophrenia, but not controls. Path analyses of average ROI activation revealed less statistically determined influence of anterior insula upon dorsal anterior cingulate bilaterally (left: χ2 = 12.73, P < .001; right: χ2 = 9.54, P = .002) during risky reward pursuit in schizophrenia.ConclusionsNAcc activation in schizophrenia varied less according to the relative riskiness of uncertain rewards compared to controls, suggesting aberrations in reward processing. The lack of activation differences in other regions suggests similar risk evaluation. Less insular influence on the anterior cingulate may relate to attenuated salience attribution or inability for risk-related brain region collaboration to sufficiently perceive situational risk.

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Insular hypocretin transmission regulates nicotine reward.

Publications

Insular hypocretin transmission regulates nicotine reward.

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