Monoaminergic neuronal changes in orexin deficient mice

Cellular Pathobiology Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute of Drug Abuse, National Institute of Health, Baltimore, MD 21224, USA.
Neuropharmacology (Impact Factor: 5.11). 09/2009; 58(4-5):826-32. DOI: 10.1016/j.neuropharm.2009.08.009
Source: PubMed


Orexin knockout (KO) mice and orexin/ataxin-3 mice (which have a different pathophysiological background in orexin deficiency) exhibit a phenotype that is similar to human narcolepsy. Although the interactions between the monoaminergic and orexinergic systems are not entirely clear, indirect monoamine-receptor agonists (especially psychostimulants) may contribute to the treatment of narcolepsy. The present study was designed to investigate the interaction between brain orexinergic and monoaminergic neurons as measured by the status of monoaminergic systems and monoamine-related behaviors using orexin-deficient mice. Previous studies have shown that a reduction of monoaminergic tone is related to wakefulness. In the present study, locomotor activity in a novel environment and dopamine turnover was significantly decreased in orexin-deficient mice compared to WT mice, which suggests that psychostimulants may be useful for maintaining wakefulness in orexin deficiency. We also examined the effects of orexin deficiency on psychostimulant-induced hyperlocomotion. The hyperlocomotion induced by methamphetamine and methylphenidate was lower, whereas that induced by MDMA was higher in orexin KO mice compared to WT mice. The sensitivities against psychostimulants in orexin/ataxin-3 mice differed from those in orexin KO mice. These results indicate that the effectiveness of each psychostimulant, which is closely related to its monoaminergic function, was influenced by orexin deficiency itself as well as by the different pathophysiological background in orexin deficiency.

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    • "In support of this proposition, a number of research groups began to evaluate the role of orexin on cocaine [19–21], nicotine [22–25], ethanol [26–31], and morphine [11, 32]. For instance, Mori et al. [33] reported that orexin mutant mice have attenuated physical withdrawal from morphine. Li et al. [11] found that after 5 days of treatment (4 mg/kg) twice a day with chronic amphetamine, cAMP-CRMB in orexin neurons was activated. "
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    ABSTRACT: This study sought to explore the degree of orexin levels in Chinese opiate and methamphetamine addicts and the differences between them. The cross-sectional study was conducted among detoxified drug addicts from Mandatory Detoxification Center (MDC) in five Chinese cities. Orexin levels were assayed with radioimmunoassay (RIA). Mann-Whitney U test and Kruskal-Wallis test were used to detect differences across groups, and logistic regression was used to explore the association between orexin levels and characteristics of demographic and drug abuse. Between November 2009 and January 2011, 285 opiates addicts, 112 methamphetamine addicts, and 79 healthy controls were enrolled. At drug withdrawal period, both opiate and methamphetamine addicts had lower median orexin levels than controls, and median orexin levels in opiate addicts were higher than those in methamphetamine addicts (all above P < 0.05). Adjusted odds of the above median concentration of orexin were higher for injection than "chasing the dragon" (AOR = 3.1, 95% CI = 1.2-7.9). No significant factors associated with orexin levels of methamphetamine addicts were found. Development of intervention method on orexin system by different administration routes especially for injected opiate addicts at detoxification phase may be significant and was welcome.
    09/2013; 2013(5):282641. DOI:10.1155/2013/282641
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    • "Activation of both receptors results in elevated levels of the intracellular Ca2+ concentrations, and this in turn results in the enhancement of the Gq-mediated stimulation of phospholipase C. Hypocretin immunoreactive cell bodies have been observed mainly in the hypothalamus [79]. Hypocretin-containing neurons have widespread projections throughout the CNS with particularly dense excitatory projections to monoaminergic and serotonergic brainstem centers [80]. The hypocretin system influences a wide range of physiological processes in mammals, such as feeding, arousal, rewards, and drug addiction [81,82]. "
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    ABSTRACT: Genetic studies have clearly shown that primary headaches (migraine, tension-type headache and cluster headache) are multifactorial disorders characterized by a complex interaction between different genes and environmental factors. Genetic association studies have highlighted a potential role in the etiopathogenesis of these disorders for several genes related to vascular, neuronal and neuroendocrine functions. A potential role as a therapeutic target is now emerging for some of these genes. The main purpose of this review is to describe new advances in our knowledge regarding the role of MTHFR, KCNK18, TRPV1, TRPV3 and HCRTR genes in primary headache disorders. Involvement of these genes in primary headaches, as well as their potential role in the therapy of these disorders, will be discussed.
    The Journal of Headache and Pain 07/2013; 14(1):61. DOI:10.1186/1129-2377-14-61 · 2.80 Impact Factor
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    • "ergic neurons in orexin / ataxin - 3 mice would be reduced during wakefulness rela - tive to wild - type mice . Surprisingly , however , serotonergic DR neurons in orexin / ataxin - 3 mice showed no differences in firing frequency in any state compared with wild - type mice . Orexin / ataxin - 3 mice have normal serotonin levels in the forebrain ( Mori et al . , 2010 ) . These results indicate that the activity of se - rotonergic DR neurons is normally highly influenced by orexin neuronal activity but , in the chronic absence of orexin input , compensation can occur ."
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    ABSTRACT: Orexin/hypocretin neurons have a crucial role in the regulation of sleep and wakefulness. To help determine how these neurons promote wakefulness, we generated transgenic mice in which orexin neurons expressed halorhodopsin (orexin/Halo mice), an orange light-activated neuronal silencer. Slice patch-clamp recordings of orexin neurons that expressed halorhodopsin demonstrated that orange light photic illumination immediately hyperpolarized membrane potential and inhibited orexin neuron discharge in proportion to illumination intensity. Acute silencing of orexin neurons in vivo during the day (the inactive period) induced synchronization of the electroencephalogram and a reduction in amplitude of the electromyogram that is characteristic of slow-wave sleep (SWS). In contrast, orexin neuron photoinhibition was ineffective during the night (active period). Acute photoinhibition of orexin neurons during the day in orexin/Halo mice also reduced discharge of neurons in an orexin terminal field, the dorsal raphe (DR) nucleus. However, serotonergic DR neurons exhibited normal discharge rates in mice lacking orexin neurons. Thus, although usually highly dependent on orexin neuronal activity, serotonergic DR neuronal activity can be regulated appropriately in the chronic absence of orexin input. Together, these results demonstrate that acute inhibition of orexin neurons results in time-of-day-dependent induction of SWS and in reduced firing rate of neurons in an efferent projection site thought to be involved in arousal state regulation. The results presented here advance our understanding of the role of orexin neurons in the regulation of sleep/wakefulness and may be relevant to the mechanisms that underlie symptom progression in narcolepsy.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 07/2011; 31(29):10529-39. DOI:10.1523/JNEUROSCI.0784-11.2011 · 6.34 Impact Factor
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