Browsing by Subject "Orexin"

Now showing 1 - 6 of 6
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    Dual Orexin Receptor Antagonist Attenuates Increases in IOP, ICP, and Translaminar Pressure Difference After Stimulation of the Hypothalamus in Rats
    (Association for Research in Vision and Ophthalmology, 2022) DeCarlo, Arthur A.; Hammes, Nathan; Johnson, Philip L.; Shekhar, Anantha; Samuels, Brian C.; Ophthalmology, School of Medicine
    Purpose: Intraocular pressure (IOP) remains the only modifiable risk factor for glaucoma progression. Our previous discovery that stimulation of nuclei within the hypothalamus can modulate IOP, intracranial pressure (ICP), and translaminar pressure difference (TLPD) fluctuations led us to investigate this pathway further. Our purpose was to determine the role of orexin neurons, primarily located in the dorsomedial hypothalamus (DMH) and perifornical (PeF) regions of the hypothalamus, in modulating these pressures. Methods: Sprague Dawley rats were pretreated systemically with a dual orexin receptor antagonist (DORA-12) at 30 mg/Kg (n = 8), 10 mg/Kg (n = 8), or vehicle control (n = 8). The IOP, ICP, heart rate (HR), and mean arterial pressure (MAP) were recorded prior to and following excitation of the DMH/PeF using microinjection of the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline methiodide (BMI). Results: Administration of the DORA at 30 mg/Kg significantly attenuated peak IOP by 5.2 ± 3.6 mm Hg (P = 0.007). During the peak response period (8-40 minutes), the area under the curve (AUC) for the 30 mg/Kg DORA cohort was significantly lower than the control cohort during the same period (P = 0.04). IOP responses for peak AUC versus DORA dose, from 0 to 30 mg/Kg, were linear (R2 = 0.18, P = 0.04). The ICP responses during the peak response period (4-16 minutes) versus DORA dose were also linear (R2 = 0.24, P = 0.014). Pretreatment with DORA significantly decreased AUC for the TLPD following stimulation of the DMH/PeF (10 mg/kg, P = 0.045 and 30 mg/kg, P = 0.015). Conclusions: DORAs have the potential to attenuate asynchronous changes in IOP and in ICP and to lessen the extent of TLPDs that may result from central nervous system (CNS) activation.
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    Eludicating triggers and neurochemical circuits underlying hot flashes in an ovariectomy model of menopause
    (2016-02-26) Federici, Lauren Michele; Shekhar, Anantha; Goodlett, Charles; Johnson, Philip L.; Oxford, Gerry S.; Rusyniak, Daniel E.
    Menopausal symptoms, primarily hot flashes, are a pressing clinical problem for both naturally menopausal women and breast and ovarian cancer patients, with a high societal and personal cost. Hot flashes are poorly understood, and animal modeling has been scarce, which has substantially hindered the development of non-hormonal treatments. An emerging factor in the hot flash experience is the role of anxiety and stress-related stimuli, which have repeatedly been shown to influence the bother, frequency, and severity of hot flashes. Causal relationships are difficult to determine in a clinical setting, and the use of animal models offers the ability to elucidate causality and mechanisms. The first part of this work details the development and validation of novel animal models of hot flashes using clinically relevant triggers (i.e., compounds or stimuli that cause hot flashes in clinical settings), which also increase anxiety symptoms. These studies revealed that these triggers elicited strong (7-9 °C) and rapid hot flash-associated increases in tail skin temperature in rats. In a surgical ovariectomy rat model of menopause, which typically exhibit anxiety-like behavior, hot flash provocation revealed an ovariectomy-dependent vulnerability, which was attenuated by estrogen replacement in tested models. An examination of the neural circuitry in response to the most robust flushing compound revealed increased cellular activity in key thermoregulatory and emotionally relevant areas. The orexin neuropeptide system was hyperactive and presented as a novel target; pretreatment with selective and dual orexin receptor antagonists significantly diminished or eliminated, respectively, the response to a hot flash provocation in ovariectomized rats. The insertion/deletion polymorphism of the serotonin transporter has been linked to increased anxiety-associated traits in humans, and subsequent studies prolonged hot flashes in SERT+/- rats, which also caused hot flashes in highly symptomatic women. These studies indicate the orexin system may be a novel non-hormonal treatment target, and future studies will determine the therapeutic importance of orexin receptor antagonists for menopausal symptoms.
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    Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation
    (Frontiers, 2017-06-09) Bonaventure, Pascal; Dugovic, Christine; Shireman, Brock; Preville, Cathy; Yun, Sujin; Lord, Brian; Nepomuceno, Diane; Wennerholm, Michelle; Lovenberg, Timothy; Carruthers, Nicolas; Fitz, Stephanie D.; Shekhar, Anantha; Johnson, Philip L.; Psychiatry, School of Medicine
    Orexin neurons originating in the perifornical and lateral hypothalamic area are highly reactive to anxiogenic stimuli and have strong projections to anxiety and panic-associated circuitry. Recent studies support a role for the orexin system and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress response. However, no selective OX1R antagonist has been systematically tested in two preclinical models of using panicogenic stimuli that induce panic attack in the majority of people with panic disorder, namely an acute hypercapnia-panic provocation model and a model involving chronic inhibition of GABA synthesis in the perifornical hypothalamic area followed by intravenous sodium lactate infusion. Here we report on a novel brain penetrant, selective and high affinity OX1R antagonist JNJ-54717793 (1S,2R,4R)-7-([(3-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-N-[5-(trifluoromethyl)pyrazin-2-yl]-7-azabicyclo[2.2.1]heptan-2-amine). JNJ-54717793 is a high affinity/potent OX1R antagonist and has an excellent selectivity profile including 50 fold versus the OX2R. Ex vivo receptor binding studies demonstrated that after oral administration JNJ-54717793 crossed the blood brain barrier and occupied OX1Rs in the rat brain. While JNJ-54717793 had minimal effect on spontaneous sleep in rats and in wild-type mice, its administration in OX2R knockout mice, selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. JNJ-54717793 attenuated CO2 and sodium lactate induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. These data confirm that selective OX1R antagonism may represent a novel approach of treating anxiety disorders, with no apparent sedative effects.
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    Hypothalamic orexin’s role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model
    (Elsevier, 2016-03) Federici, Lauren M.; Caliman, Izabela Facco; Molosh, Andrei I.; Fitz, Stephanie D.; Truitt, William A.; Bonaventure, Pascal; Carpenter, Janet S.; Shekhar, Anantha; Johnson, Philip L.; Department of Psychiatry, IU School of Medicine
    Distressing symptoms such as hot flashes and sleep disturbances affect over 70% of women approaching menopause for an average of 4-7 years, and recent large cohort studies have shown that anxiety and stress are strongly associated with more severe and persistent hot flashes and can induce hot flashes. Although high estrogen doses alleviate symptoms, extended use increases health risks, and current non-hormonal therapies are marginally better than placebo. The lack of effective non-hormonal treatments is largely due to the limited understanding of the mechanisms that underlie menopausal symptoms. One mechanistic pathway that has not been explored is the wake-promoting orexin neuropeptide system. Orexin is exclusively synthesized in the estrogen receptor rich perifornical hypothalamic region, and has an emerging role in anxiety and thermoregulation. In female rodents, estrogens tonically inhibit expression of orexin, and estrogen replacement normalizes severely elevated central orexin levels in postmenopausal women. Using an ovariectomy menopause model, we demonstrated that an anxiogenic compound elicited exacerbated hot flash-associated increases in tail skin temperature (TST, that is blocked with estrogen), and cellular responses in orexin neurons and efferent targets. Furthermore, systemic administration of centrally active, selective orexin 1 or 2 and dual receptor antagonists attenuated or blocked TST responses, respectively. This included the reformulated Suvorexant, which was recently FDA-approved for treating insomnia. Collectively, our data support the hypothesis that dramatic loss of estrogen tone during menopausal states leads to a hyperactive orexin system that contributes to symptoms such as anxiety, insomnia, and more severe hot flashes. Additionally, orexin receptor antagonists may represent a novel non-hormonal therapy for treating menopausal symptoms, with minimal side effects.
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    Nucleus Accumbens Shell Orexin-1 Receptors Are Not Needed For Single-Bottle Limited Daily Access Alcohol Intake in C57BL/6 mice
    (Elsevier, 2020-12) Lei, Kelly; Kwok, Claudina; Hopf, Frederic W.; Psychiatry, School of Medicine
    Excessive, binge drinking is a major contributor to the great harm and cost of alcohol use disorder. We recently showed, using both limited and intermittent-access two-bottle-choice models, that inhibiting nucleus accumbens shell (Shell) orexin-1-receptors (Ox1Rs) reduces alcohol intake in higher-drinking male C57BL/6 mice (Lei et al., 2019). Other studies implicate Ox1Rs, tested systemically, for several higher-drinking models, including the single-bottle, Rhodes Drinking-in-the-Dark paradigm. Here, we report studies examining whether Shell Ox1Rs contribute to alcohol intake in male mice using a single-bottle Limited Daily Access (LDA) drinking model modified from drinking-in-the-dark paradigms (2-h access starting 3 h into the dark cycle, 5 days per week). In addition, some previous work has suggested possible differences in circuitry for one- versus two-choice behaviors, and thus other mice first drank under a single-bottle schedule, and then an additional water bottle was included 2 days a week starting in week 3. Surprisingly, at the same time we were determining Ox1R importance for two-bottle-choice models, parallel studies found that inhibiting Shell Ox1Rs had no impact on drinking using the single-bottle LDA model, or when a second bottle containing water was added later during drinking. Furthermore, we have related Shell Ox1R regulation of intake to basal consumption, but no such pattern was observed with single-bottle LDA drinking. Thus, unlike our previous work showing the importance of Shell Ox1Rs for male alcohol drinking under several two-bottle-choice models, Shell Ox1Rs were not required under a single-bottle paradigm, even if a second water-containing bottle was later added. These results raise the speculations that different mechanisms could promote intake under single- versus two-bottle access conditions, and that the conditions under which an animal learns to drink can impact circuitry driving future intake.
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    OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES
    (Wiley, 2015-09) Johnson, Philip L.; Federici, Lauren M.; Fitz, Stephanie D.; Renger, John J.; Shireman, Brock; Winrow, Christopher J.; Bonaventure, Pascal; Shekhar, Anantha; Department of Anatomy & Cell Biology, IU School of Medicine
    BACKGROUND: The neuropeptides orexin A and B play a role in reward and feeding and are critical for arousal. However, it was not initially appreciated that most prepro-orexin synthesizing neurons are almost exclusively concentrated in the perifornical hypothalamus, which when stimulated elicits panic-associated behavior and cardiovascular responses in rodents and self-reported "panic attacks" and "fear of dying" in humans. More recent studies support a role for the orexin system in coordinating an integrative stress response. For instance, orexin neurons are highly reactive to anxiogenic stimuli, are hyperactive in anxiety pathology, and have strong projections to anxiety and panic-associated circuitry. Although the two cognate orexin receptors are colocalized in many brain regions, the orexin 2 receptor (OX2R) most robustly maps to the histaminergic wake-promoting region, while the orexin 1 receptor (OX1R) distribution is more exclusive and dense in anxiety and panic circuitry regions, such as the locus ceruleus. Overall, this suggests that OX1Rs play a critical role in mobilizing anxiety and panic responses. METHODS: Here, we used a CO2 -panic provocation model to screen a dual OX1/2R antagonist (DORA-12) to globally inhibit orexin activity, then a highly selective OX1R antagonist (SORA1, Compound 56) or OX2R antagonist (SORA2, JnJ10397049) to assess OX1R and OX2R involvement. RESULTS: All compounds except the SORA2 attenuated CO2 -induced anxiety-like behaviors, and all but the SORA2 and DORA attenuated CO2 -induced cardiovascular responses. CONCLUSIONS: SORA1s may represent a novel method of treating anxiety disorders, with no apparent sedative effects that were present with a benzodiazepine.