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Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.
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investigation of the effect of the dual orexin receptor antagonist Almorexant on ophthalmological spermatogenic and hormonal variables in healthy male subjects
Biomedicine & Pharmacotherapy, 2021Co-Authors: Jasper Dingemanse, Jed Black, Pascal Charef, Chris GouwsAbstract:Abstract Background/Aims The aim of this single-center, double-blind study was to investigate the effect of a 4-week once daily administration of 200 mg Almorexant on tear film break-up time, spermatogenesis, hormone levels, and pancreatic elastase in stool in healthy male subjects. Methods Almorexant 200 mg or matching placebo was administered in the evening for 4 weeks once daily to 56 healthy male subjects. Changes in ophthalmological variables, sperm composition, hormone levels, and pancreatic elastase levels in stool were evaluated periodically up to 8 weeks after discontinuation of drug administration. Blood samples for pharmacokinetic measurements were taken after 4 weeks to confirm compliance to study drug intake. Results The results of this study revealed no treatment effects of Almorexant, neither on tear film break-up time nor on other ophthalmological variables investigated during this study. Furthermore, spermatogenesis, hormones of the hypothalamic-pituitary-adrenal and –gonadal axes, and endocrine pancreatic secretion were shown to be not affected by a 4-week once daily administration of Almorexant. Conclusion Almorexant was well tolerated and had no effect on the spectrum of pharmacodynamic variables assessed. Ophthalmology and testicular findings detected in preclinical studies were not observed in this clinical study. Therefore, these preclinical findings appear not to be relevant for humans and do not prevent from conducting larger clinical trials with either healthy subjects or patients.
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Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with Almorexant
The Journal of Clinical Pharmacology, 2014Co-Authors: Matthias Hoch, Joop M. A. Van Gerven, Helene C. Van Gorsel, Jasper DingemanseAbstract:A double-blind, placebo- and active comparator-controlled, randomized, single-ascending-dose study was conducted to investigate the safety, pharmacokinetics, and pharmacodynamics of ACT-462206, a novel dual orexin receptor antagonist. Healthy male subjects received single oral doses of 5, 25, 100, 200, 400, 1,000, and 1,500 mg ACT-462206 (n = 6 per group) or placebo (n = 2 per group). In addition, subjects in the 400-mg group received a single oral dose of 400 mg Almorexant (two-way crossover). ACT-462206 was generally well tolerated. Sleepiness, headache, and fatigue were the most frequently reported adverse events. The incidence of sleepiness appeared dose-dependent. ACT-462206 was absorbed with a median tmax of 1.5-4.0 hours. The elimination half-life varied from 4.8 to 11.2 hours. A clinically relevant reduction in vigilance and attention, alertness, and motor coordination was recorded at ACT-462206 doses ≥200 mg. The onset was between 20 and 45 minutes after drug intake, the maximum effect between 1 and 2 hours after drug administration, and these impairing effects largely disappeared within 8 hours post-dose. Doses of 400-1,000 mg ACT-462206 were similarly efficacious to 400 mg Almorexant, with a trend for an earlier onset of action with ACT-462206. The present results confirm the activity of ACT-462206 as an orexin antagonist.
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Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of Almorexant and zolpidem in recreational drug users.
CNS Drugs, 2014Co-Authors: Hans G. Cruz, Petra Hoever, Bijan Chakraborty, Kerri A. Schoedel, Edward M. Sellers, Jasper DingemanseAbstract:Background Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders.
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validation of an lc ms ms method for the quantitative determination of the orexin receptor antagonist Almorexant and its four primary metabolites in human plasma
Journal of Chromatography B, 2014Co-Authors: Winfried Wagnerredeker, Isabel Finsterwald, Jasper DingemanseAbstract:A sensitive and selective LC-MS/MS method has been developed to quantify Almorexant and its four primary metabolites M3, M5, M6, and M8 in human plasma samples. The method involved protein precipitation with acetonitrile in the high calibration range and liquid/liquid extraction with ethyl acetate in the low calibration range. Labeled internal standards were available for four analytes. Separation was performed with an Eclipse XDB-C18 (2.1mm×150mm, particle size 3.5μm) and a XBridge C18 column (2.1mm×50mm, particle size 3.5μm). The mobile phases were mixtures of acetonitrile, methanol, and water containing 1% formic acid; flow rate was 400μL/min. The triple stage quadrupole mass spectrometer was operated in ESI mode and the methods were linear over a range of 0.400-100ng/mL (Almorexant, M5, M6), 1.00-100ng/mL (M3, M8), and 50.0-1000ng/mL (all analytes). The inter-day coefficients of variation were equal to or smaller than 10.5%. The inter-day accuracies were between 92.1% and 105.2%. The validated method was successfully applied to the pharmacokinetic assessment of Almorexant and its metabolites in several phase I studies.
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Pharmacokinetic and pharmacodynamic interactions between Almorexant, a dual orexin receptor antagonist, and desipramine
European Neuropsychopharmacology, 2014Co-Authors: Hans G. Cruz, Petra Hoever, Joop M. A. Van Gerven, Justin L. Hay, Federica Alessi, Erik T. Te Beek, Jasper DingemanseAbstract:Abstract Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by Almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between Almorexant and desipramine. Almorexant 200 mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50 mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that Almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of Almorexant. Pharmacodynamic evaluations indicated that Almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, Almorexant and desipramine in combination showed the same pharmacodynamic profile as Almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of Almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of Almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics.
Francois Jenck - One of the best experts on this subject based on the ideXlab platform.
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the use of physiology based pharmacokinetic and pharmacodynamic modeling in the discovery of the dual orexin receptor antagonist act 541468
Journal of Pharmacology and Experimental Therapeutics, 2017Co-Authors: Alexander Treiber, John Gatfield, Christoph Boss, Joop M. A. Van Gerven, Markus Von Raumer, Ruben De Kanter, Catherine Roch, Benno Schindelholz, Clemens Muehlan, Francois JenckAbstract:The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 and OX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, Almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.
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structure activity relationship biological and pharmacological characterization of the proline sulfonamide act 462206 a potent brain penetrant dual orexin 1 orexin 2 receptor antagonist
ChemMedChem, 2014Co-Authors: Christoph Boss, Hendrik Dietrich, Thierry Sifferlen, Alexander Treiber, Francois Jenck, Christine Brotschi, Catherine Rochbrisbare, Michel A Steiner, Markus Von Raumer, Bibia HeidmannAbstract:The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (Almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.
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structure activity relationship studies and sleep promoting activity of novel 1 chloro 5 6 7 8 tetrahydroimidazo 1 5 a pyrazine derivatives as dual orexin receptor antagonists part 2
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: Thierry Sifferlen, Ralf Koberstein, Catherine Brisbareroch, Emmanuelle Cottreel, John Gatfield, Francois Jenck, Thomas Weller, Amandine Boller, Christoph BossAbstract:Replacement of the dimethoxyphenyl moiety in the core skeleton of Almorexant by appropriately substituted imidazoles afforded novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as potent dual orexin receptor antagonists. We describe in this Letter our efforts to further optimize the potency and brain penetration of these derivatives by fine-tuning of the pivotal phenethyl motif, and we comment on the sleep-promoting activity of selected compounds in a rat electroencephalographic (EEG) model.
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examining the role of endogenous orexins in hypothalamus pituitary adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat
Psychoneuroendocrinology, 2013Co-Authors: Michel A Steiner, Catherine Brisbareroch, Daniel S Strasser, Carla Sciarretta, Rolf Studer, Francois JenckAbstract:Summary The orexin neuropeptide system regulates wakefulness and contributes to physiological and behavioral stress responses. Moreover, a role for orexins in modulating hypothalamus–pituitary–adrenal (HPA) axis activity has been proposed. Brain penetrating dual orexin receptor (OXR) antagonists such as Almorexant decrease vigilance and have emerged as a novel therapeutic class for the treatment of insomnia. Almorexant was used here as a pharmacological tool to examine the role of endogenous orexin signaling in HPA axis endocrine function under natural conditions. After confirming the expression of prepro-orexin and OXR-1 and OXR-2 mRNA in hypothalamus, pituitary and adrenal glands, the effects of systemic Almorexant were investigated on peripheral HPA axis hormone release in the rat under baseline, stress and pharmacological challenge conditions. Almorexant did not alter basal or stress-induced corticosterone release despite affecting wake and sleep stages (detected by radiotelemetric electroencephalography/electromyography) during the stress exposure. Moreover, Almorexant did not affect the release of adrenocorticotropin (ACTH) and corticosterone at different time points along the diurnal rhythm, nor corticotrophin-releasing hormone (CRH)- and ACTH-stimulated neuroendocrine responses, measured in vivo under stress-free conditions. These results illustrate that dual OXR antagonists, despite modulating stress-induced wakefulness, do not interfere with endocrine HPA axis function in the rat. They converge to suggest that endogenous orexin signaling plays a minor role in stress hormone release under basal conditions and under challenge.
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the dual orexin receptor antagonist Almorexant alone and in combination with morphine cocaine and amphetamine on conditioned place preference and locomotor sensitization in the rat
The International Journal of Neuropsychopharmacology, 2013Co-Authors: Michel A Steiner, Hugues Lecourt, Francois JenckAbstract:Dual orexin receptor (OXR) antagonists emerge as a novel therapeutic class to treat insomnia that, based on anti-addictive effects of selective OXR type 1 antagonists in rats, might be associated with less abuse liability than commonly used γ-aminobutyric acid (GABA) receptor modulators. Here, we studied the effects of the sleep-enabling dual OXR antagonist Almorexant on conditioned place preference (CPP) and locomotor sensitization in rats. First, we compared Almorexant to the GABA metabolite γ-hydroxybutyrate (GHB), which is clinically used as a sleep-inducing drug and which is associated with mild abuse liability. Whereas conditioning with GHB induced significant place preference, conditioning with Almorexant did not. Second, we tested the potential of Almorexant to interfere with the conditioned rewarding or locomotor sensitizing effects related to psychostimulants or opiates. Almorexant attenuated the expression of CPP to high doses of cocaine (15 mg/kg) and d.l-amphetamine (2 mg/kg), but not to high dose of morphine (10 mg/kg). Conversely, Almorexant interfered with the expression of locomotor sensitization to morphine, but not with that to cocaine and d.l-amphetamine. Third, we observed that chronic Almorexant (12 d) treatment in morphine, cocaine or amphetamine pre-conditioned and locomotor-sensitized rats had no influence on the maintenance of CPP and locomotor sensitization when tested after Almorexant washout. Our findings suggest that Almorexant itself does not exert conditioned rewarding effects in the rat and that it may acutely interfere with the expression of CPP or locomotor sensitization in a drug-dependent manner (monoaminergic psychostimulants vs. opiates).
Petra Hoever - One of the best experts on this subject based on the ideXlab platform.
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Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of Almorexant and zolpidem in recreational drug users.
CNS Drugs, 2014Co-Authors: Hans G. Cruz, Petra Hoever, Bijan Chakraborty, Kerri A. Schoedel, Edward M. Sellers, Jasper DingemanseAbstract:Background Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders.
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Pharmacokinetic Interactions Between the Orexin Receptor Antagonist Almorexant and the CYP3A4 Inhibitors Ketoconazole and Diltiazem
Journal of Pharmaceutical Sciences, 2014Co-Authors: Jasper Dingemanse, Hans G. Cruz, Martine Gehin, Petra HoeverAbstract:ABSTRACT Almorexant, a tetrahydroisoquinoline orexin receptor antagonist and first representative of a new class of compounds for the treatment of insomnia, is a substrate of the cytochrome P450 3A4 isoenzyme (CYP3A4). Two randomized two-way crossover studies were performed in healthy subjects investigating the pharmacokinetic interaction between Almorexant and the CYP3A4 inhibitors ketoconazole and diltiazem. When administered as a single dose of 100 mg Almorexant during steady state of ketoconazole (400 mg once daily for 14 days) or diltiazem treatment (300 mg once daily for 11 days), the exposure to Almorexant was 10.5- and 3.5-fold, respectively, greater when compared with Almorexant alone. Exposure to the phenol metabolites M3 and M8 increased in the presence of the CYP3A4 inhibitors, whereas that to M6 (dealkylated metabolite) decreased. Concomitant ketoconazole decreased formation of the dehydrogenated metabolite M5 and diltiazem increased concentrations of this metabolite. Higher Almorexant exposure was associated with an increased incidence of typical Almorexant-related adverse events such as fatigue (both studies) and somnolence (ketoconazole study only). The present results indicate that dose adaptation must be considered when Almorexant would be coadministered with inhibitors of CYP3A4. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
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Pharmacokinetic and pharmacodynamic interactions between Almorexant, a dual orexin receptor antagonist, and desipramine
European Neuropsychopharmacology, 2014Co-Authors: Hans G. Cruz, Petra Hoever, Joop M. A. Van Gerven, Justin L. Hay, Federica Alessi, Erik T. Te Beek, Jasper DingemanseAbstract:Abstract Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by Almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between Almorexant and desipramine. Almorexant 200 mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50 mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that Almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of Almorexant. Pharmacodynamic evaluations indicated that Almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, Almorexant and desipramine in combination showed the same pharmacodynamic profile as Almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of Almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of Almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics.
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Formulation development for the orexin receptor antagonist Almorexant: assessment in two clinical studies.
Drug Design Development and Therapy, 2014Co-Authors: Jasper Dingemanse, Hans G. Cruz, Martine Gehin, Petra HoeverAbstract:Almorexant, a dual orexin receptor antagonist, was investigated for the treatment of insomnia. The following observations initiated further formulation development: the active pharmaceutical ingredient (API) was sticking to the apparatus used during tablet compression; Almorexant has an absolute bioavailability of 11.2%; and Almorexant modestly decreased the latency to persistent sleep by 10.4 minutes in patients. Two randomized crossover studies were performed to investigate the pharmacokinetics of several new formulations in healthy subjects. In study I, the old “sticky” tablet was compared to two new formulations developed to prevent sticking: a qualitatively similar tablet but with a larger API crystal size and a tablet with 30% more excipients as well as a larger API crystal size. This latter formulation was available in two strengths. The geometric mean ratios and 90% confidence interval of the area under the curve (AUC) were within the bioequivalence range of 0.80–1.25 for the different comparisons between formulations. In study II, 100 mg of the reference tablet was compared to 25 and 50 mg of a liquid-filled hard gelatin capsule developed to increase the bioavailability of Almorexant. The geometric mean ratios of the maximum concentration and AUC comparing the new 25 and 50 mg capsule formulations to the reference tablet did not exceed 0.25 and 0.50, respectively, indicating that the new capsule formulation did not increase the maximum concentration of or the total exposure to Almorexant. In conclusion, a new tablet was developed but formulation development aimed at increasing the bioavailability of Almorexant failed.
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absence of pharmacokinetic and pharmacodynamic interactions between Almorexant and warfarin in healthy subjects
Drugs in R & D, 2013Co-Authors: Jasper Dingemanse, Petra HoeverAbstract:Background and Objective Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between Almorexant and warfarin.
Roger A L Dampney - One of the best experts on this subject based on the ideXlab platform.
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blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro or chemoreceptor reflex responses
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2012Co-Authors: Kamon Iigaya, Jouji Horiuchi, Lachlan M Mcdowall, Yusuf Sediqi, Jaimie W Polson, Pascal Carrive, Roger A L DampneyAbstract:Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces...
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blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro or chemoreceptor reflex responses
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2012Co-Authors: Kamon Iigaya, Jouji Horiuchi, Lachlan M Mcdowall, Yusuf Sediqi, Jaimie W Polson, Pascal Carrive, Alex C B Lam, Roger A L DampneyAbstract:Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces marked cardiovascular and respiratory effects. Central administration of orexin can produce cardiorespiratory effects, but the extent to which orexin contributes to such responses evoked from the perifornical hypothalamus is not clear. To determine this, we used the dual orexin receptor antagonist Almorexant to challenge the cardiorespiratory effects evoked by disinhibition of the perifornical hypothalamus. Bicuculline (10 and 20 pmol) was microinjected in the perifornical area before and after administration of Almorexant (15 mg/kg iv) or vehicle in urethane-anesthetized rats. Almorexant significantly reduced the pressor, tachycardic, renal sympathoexcitatory, and tachypneic responses to bicuculline (10 pmol, by 55%, 53%, 28%, 77%; 20 pmol, by 54%, 27%, 51%, 72%, respectively). Reductions of similar magnitude were observed with bicuculline microinjections centered on more caudal sites just peripheral to the orexin neuron group, which would likely have activated fewer orexin neurons. In contrast, Almorexant had no effect on the cardiorespiratory response of the chemoreflex (sodium cyanide injection) or the sympathetic component of the baroreflex. Thus orexin makes a major contribution to the cardiorespiratory response evoked from the perifornical area even though orexin neurons represent only a fraction of the output of this area. Orexin neurons may also mediate cardiorespiratory responses from non-orexin neurons in the caudal hypothalamus. However, under resting conditions, blockade of orexin receptors does not affect the chemo- and baroreflexes.
Kamon Iigaya - One of the best experts on this subject based on the ideXlab platform.
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blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro or chemoreceptor reflex responses
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2012Co-Authors: Kamon Iigaya, Jouji Horiuchi, Lachlan M Mcdowall, Yusuf Sediqi, Jaimie W Polson, Pascal Carrive, Roger A L DampneyAbstract:Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces...
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blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro or chemoreceptor reflex responses
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2012Co-Authors: Kamon Iigaya, Jouji Horiuchi, Lachlan M Mcdowall, Yusuf Sediqi, Jaimie W Polson, Pascal Carrive, Alex C B Lam, Roger A L DampneyAbstract:Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces marked cardiovascular and respiratory effects. Central administration of orexin can produce cardiorespiratory effects, but the extent to which orexin contributes to such responses evoked from the perifornical hypothalamus is not clear. To determine this, we used the dual orexin receptor antagonist Almorexant to challenge the cardiorespiratory effects evoked by disinhibition of the perifornical hypothalamus. Bicuculline (10 and 20 pmol) was microinjected in the perifornical area before and after administration of Almorexant (15 mg/kg iv) or vehicle in urethane-anesthetized rats. Almorexant significantly reduced the pressor, tachycardic, renal sympathoexcitatory, and tachypneic responses to bicuculline (10 pmol, by 55%, 53%, 28%, 77%; 20 pmol, by 54%, 27%, 51%, 72%, respectively). Reductions of similar magnitude were observed with bicuculline microinjections centered on more caudal sites just peripheral to the orexin neuron group, which would likely have activated fewer orexin neurons. In contrast, Almorexant had no effect on the cardiorespiratory response of the chemoreflex (sodium cyanide injection) or the sympathetic component of the baroreflex. Thus orexin makes a major contribution to the cardiorespiratory response evoked from the perifornical area even though orexin neurons represent only a fraction of the output of this area. Orexin neurons may also mediate cardiorespiratory responses from non-orexin neurons in the caudal hypothalamus. However, under resting conditions, blockade of orexin receptors does not affect the chemo- and baroreflexes.