Hypocretin/Orexin Excites Hypocretin Neurons via a Local Glutamate Neuron—A Potential Mechanism for Orchestrating the Hypothalamic Arousal System

Liu, Ying; Gao, Xiao‐Bing; Sakurai, Takeshi; Pol, Anthony N. van den

doi:10.1016/s0896-6273(02)01132-7

Cited by 415 publications

(387 citation statements)

References 60 publications

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“…Although it was unexpected that the LC and DR did not increase Fos expression in response to SD in VEH-treated animals, the mixed downstream effects of NE and generally inhibitory effects of 5HT on other wakepromoting cell groups (Brown et al, 2012;Li et al, 2002;Li and van den Pol, 2005) contrast with the excitatory effects of Hcrt, HA, and ACh on these groups , suggesting that the LC and DR may be differentially regulated. The elevated Fos expression observed in the LC following forced wakefulness in ZOL but not VEH or ALM treatment groups is also surprising considering the inhibitory effect of ZOL in other regions, but this may be a result of the greatly increased level of stimulation required to keep ZOLtreated rats awake during forced wakefulness coupled with the high sensitivity of Fos expression in the LC to stress (Sved et al, 2002).…”

Section: Discussionmentioning

confidence: 96%

“…All-known wake-promoting cell groups express HcrtRs and are innervated by Hcrt neurons Eggermann et al, 2001;Eriksson et al, 2001;Li et al, 2002;Marcus et al, 2001;Peyron et al, 1998;Yamanaka et al, 2002). If ALM were to promote sleep through inhibition of downstream targets, it would be expected to interfere with the activation of wake-promoting cell groups.…”

Section: Discussionmentioning

confidence: 99%

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The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wakepromoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH-or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos + cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH-and ALMtreated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL-but not in VEH-or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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“…In addition, hypocretin/orexin (hcrt/orx) neurons reside in the LHA and are activated (Fos-ir) following copulation, and the numbers of hcrt/orx neurons decreased after castration (Muschamp et al, 2007). Furthermore, 5-HT inhibits hcrt/orx neurons in the LHA (Li et al, 2002). Therefore, a possible way in which LHA 5-HT inhibits sexual behavior is by inhibiting hcrt/orx neurons, which would remove their facilitative effect on VTA DA cell firing (Muschamp et al, 2007).…”

Section: Ne Antagonists − (Clark and Smith 1990)mentioning

confidence: 99%

Sexual behavior in male rodents

Hull

Domínguez

2007

Hormones and Behavior

388

272

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The hormonal factors and neural circuitry that control copulation are similar across rodent species, although there are differences in specific behavior patterns. Both estradiol (E) and dihydrotestosterone (DHT) contribute to the activation of mating, although E is more important for copulation and DHT for genital reflexes. Hormonal activation of the medial preoptic area (MPOA) is most effective, although implants in the medial amygdala (MeA) can also stimulate mounting in castrates. Chemosensory inputs from the main and accessory olfactory systems are the most important stimuli for mating in rodents, especially in hamsters, although genitosensory input also contributes. Dopamine agonists facilitate sexual behavior, and serotonin (5-HT) is generally inhibitory, though certain 5-HT receptor subtypes facilitate erection or ejaculation. Norepinephrine agonists and opiates have dose-dependent effects, with low doses facilitating and high doses inhibiting behavior.

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“…Thus, it is possible that this subpopulation of DA neurons display a greater sensitivity to salient environmental stimuli and/or HCRT-1 than other, non-PFCprojecting, DA neurons. Finally, ICV infusion of HCRT may activate LH HCRT neurons via neighboring glutamatergic neurons (Li et al, 2002), which project both to VTA and PFC, but only sparsely to Acc (Fadel and Deutch, 2002).…”

Section: Circuitry Underlying Selective Increase In Da Efflux By Hcrtmentioning

confidence: 99%

Hypocretin/Orexin Selectively Increases Dopamine Efflux within the Prefrontal Cortex: Involvement of the Ventral Tegmental Area

Vittoz

Berridge

2005

Neuropsychopharmacol

164

114

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Hypocretins (HCRTs) modulate a variety of behavioral and physiological processes, in part via interactions with multiple ascending modulatory systems. Further, HCRT efferents from the lateral hypothalamus innervate midbrain dopamine (DA) nuclei, and DA cell bodies express HCRT receptors. Combined, these observations suggest that HCRT may influence behavioral state and/or statedependent processes via modulation of DA neurotransmission. The current studies used in vivo microdialysis in the unanesthetized rat to first characterize the effect of intracerebroventricular infusion of HCRT-1 (0.07, 0.7 nmol) on extracellular levels of DA within the prefrontal cortex (PFC) and nucleus accumbens (Acc). Electroencephalographic/electromyographic measures of sleep-wake state were collected along with select behavioral measures (eg locomotor activity, grooming). HCRT-1 dose-dependently increased PFC dialysate DA levels, and these increases were closely correlated with increases in time spent awake. In contrast, Acc DA levels were unaffected. Additional studies examined whether HCRT-1 acts directly within the ventral tegmental area (VTA) to selectively increase PFC DA efflux and modulate behavioral state. Unilateral infusion of HCRT-1 (0.1, 1.0 nmol) within the VTA increased PFC, but not Acc, DA levels. Importantly, intra-VTA infusion of HCRT-1 increased the time spent awake and grooming. Moreover, HCRT-induced increases in both time spent awake and time spent grooming were significantly correlated with post-infusion PFC DA levels. The current observations predict a prominent modulatory influence of HCRT on PFC-dependent cognitive and affective processes that results, in part, from actions within the VTA. Additionally, these observations suggest that the activation of VTA DA neurons contributes to the behavioral state-modulatory actions of HCRT.

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Hypocretin/Orexin Excites Hypocretin Neurons via a Local Glutamate Neuron—A Potential Mechanism for Orchestrating the Hypothalamic Arousal System

Cited by 415 publications

References 60 publications

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Sexual behavior in male rodents

Hypocretin/Orexin Selectively Increases Dopamine Efflux within the Prefrontal Cortex: Involvement of the Ventral Tegmental Area

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