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Orexin and motivation

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https://www.readbyqxmd.com/read/29129052/synthesis-and-evaluation-of-orexin-1-receptor-antagonists-with-improved-solubility-and-cns-permeability
#1
David A Perrey, Ann M Decker, Yanan Zhang
Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies...
November 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29089444/pre-synaptic-regulation-of-leptin-in-a-defined-lateral-hypothalamus-ventral-tegmental-area-neurocircuitry-depends-on-energy-state
#2
Jing-Jing Liu, Nicholas T Bello, Zhiping P Pang
Synaptic transmission controls information flow in the brain and expression of all brain-related behaviors, including food intake. Leptin, an adipocyte-derived hormone, acts on neurons located in the lateral hypothalamus (LHA) to maintain energy homeostasis and regulate food intake behavior. The specific synaptic mechanisms, cell types and neural projections mediating this effect remain unclear. In male mice, using pathway-specific retrograde tracing, whole cell patch clamp recordings and posthoc cell type identification, we found that leptin reduces excitatory synaptic strength onto both melanin-concentrating hormone (MCH) and orexin-expressing neurons projecting from the LHA to the ventral tegmental area (VTA), which may affect dopamine signaling and motivation for feeding...
October 31, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29073109/opioid-and-orexin-hedonic-hotspots-in-rat-orbitofrontal-cortex-and-insula
#3
Daniel C Castro, Kent C Berridge
Hedonic hotspots are brain sites where particular neurochemical stimulations causally amplify the hedonic impact of sensory rewards, such as "liking" for sweetness. Here, we report the mapping of two hedonic hotspots in cortex, where mu opioid or orexin stimulations enhance the hedonic impact of sucrose taste. One hedonic hotspot was found in anterior orbitofrontal cortex (OFC), and another was found in posterior insula. A suppressive hedonic coldspot was also found in the form of an intervening strip stretching from the posterior OFC through the anterior and middle insula, bracketed by the two cortical hotspots...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29052613/dynorphin-counteracts-orexin-in-the-paraventricular-nucleus-of-the-thalamus-cellular-and-behavioral-evidence
#4
Alessandra Matzeu, Marsida Kallupi, Olivier George, Paul Schweitzer, Rémi Martin-Fardon
The orexin (Orx) system plays a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orx and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Previous studies suggested that OrxA transmission in the posterior paraventricular nucleus of the thalamus (pPVT) participates in cocaine-seeking behavior. This study determined whether Orx and Dyn interact in the pPVT...
October 20, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28858406/chemogenetic-activation-of-the-lateral-hypothalamus-reverses-early-life-stress-induced-deficits-in-motivational-drive
#5
Erin J Campbell, Caitlin S Mitchell, Cameron D Adams, Jiann Wei Yeoh, Deborah M Hodgson, Brett A Graham, Christopher V Dayas
Altered motivated behaviour is a cardinal feature of several neuropsychiatric conditions including mood disorders. One well-characterized antecedent to the development of mood disorders is exposure to early life stress (ELS). A key brain substrate controlling motivated behaviour is the lateral hypothalamus (LH). Here, we examined the effect of ELS on LH activation and the motivation to self-administer sucrose. We tested whether chemogenetic activation of LH circuits could modify sucrose responding in ELS rats and examined the impact on LH cell populations...
October 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28741623/effects-of-suvorexant-a-dual-orexin-hypocretin-receptor-antagonist-on-impulsive-behavior-associated-with-cocaine
#6
Taylor A Gentile, Steven J Simmons, Mia N Watson, Krista L Connelly, Eugen Brailoiu, Yanan Zhang, John W Muschamp
Hypothalamic hypocretin (orexin) peptides mediate arousal, attention, and reward processing. Fibers containing orexins project to brain structures that govern motivated behavior, including the ventral tegmental area (VTA). A number of psychiatric conditions, including attention deficit hyperactivity disorder (ADHD) and substance use disorders, are characterized by deficits in impulse control, however the relationship between orexin and impulsive behavior is incompletely characterized. The effects of systemic or centrally administered orexin receptor (OXR) antagonists on measures of impulsive-like behavior in rats were evaluated using the five-choice serial reaction time task (5-CSRTT) and delay discounting procedures...
July 25, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28705440/inhibition-of-trkb-at-the-nucleus-accumbens-using-ana-12-regulates-basal-and-stress-induced-orexin-a-expression-within-the-mesolimbic-system-and-affects-anxiety-sociability-and-motivation
#7
Idu Azogu, Helene Plamondon
Repeated stress exposure can lead to the development of anxiety and mood disorders. An emerging biological substrate of depression and associated pathology is the nucleus accumbens (NAc), which through interactions with limbic, cognitive and motor circuits can regulate a variety of stress responses. Within these circuits, orexin neurons are involved in arousal and stress adaptability, effects proposed mediated via brain-derived neurotrophic factor signaling. This study tested the hypotheses that 1) repeated exposure to heterotypic stress alters social ability and preference and passive avoidant behaviors, 2) TrkB receptors at the NAc shell regulates stress-induced behavioral responses and orexin expression within the mesocorticolimbic system...
July 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28663114/palatable-food-self-administration-and-reinstatement-are-not-affected-by-dual-orexin-receptor-antagonism
#8
Shaun Yon-Seng Khoo, Kelly J Clemens, Gavan P McNally
The orexins are widely regarded potential therapeutic targets for a range of disorders of appetitive motivation, including obesity. The motivational activator theory, the first coherent account of the orexin system's role in appetitive motivation, predicts that orexin release motivates appetitive behaviour when the reinforcer is highly salient, available under a high unit-cost or when reward seeking is cue-driven. The present study tested the effect of intracerebroventricular (i.c.v.) administration of the highly potent and commercially available dual orexin receptor antagonist, TCS 1102, on self-administration and reinstatement of palatable food seeking in hungry and sated rats...
June 27, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28631980/orexin-research-patent-news-from-2016
#9
REVIEW
Christoph Boss, Catherine Roch
The orexin system consists of two G-protein-coupled receptors, orexin 1 and orexin 2 and two endogenous ligands, orexin A and orexin B . It is evolutionarily highly conserved. It is involved in the promotion of wakefulness as well as in anxiety and addictive disorders. In addition, its activation via the Ox1 receptor triggers apoptosis in several cancer cell lines. Dual orexin receptor antagonists are successfully used to treat primary insomnia. The major open questions are now related to the clinical validation of Ox1 selective antagonists...
October 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28630298/hypocretin-orexin-is-critical-in-sustaining-theta-gamma-rich-waking-behaviors-that-drive-sleep-need
#10
Anne Vassalli, Paul Franken
Hcrt gene inactivation in mice leads to behavioral state instability, abnormal transitions to paradoxical sleep, and cataplexy, hallmarks of narcolepsy. Sleep homeostasis is, however, considered unimpaired in patients and narcoleptic mice. We find that whereas Hcrt(ko/ko) mice respond to 6-h sleep deprivation (SD) with a slow-wave sleep (SWS) EEG δ (1.0 to 4.0 Hz) power rebound like WT littermates, spontaneous waking fails to induce a δ power reflecting prior waking duration. This correlates with impaired θ (6...
July 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28419646/suvorexant-an-orexin-hypocretin-receptor-antagonist-attenuates-motivational-and-hedonic-properties-of-cocaine
#11
Taylor A Gentile, Steven J Simmons, David J Barker, Jessica K Shaw, Rodrigo A España, John W Muschamp
Orexins ('hypocretins') are peptides produced by neurons of the hypothalamus that project to structures implicated in reward and emotion processing. Converging evidence demonstrates functional roles of orexin signaling in arousal, sleep/wakefulness and motivated behaviors for natural and drug rewards. Suvorexant, a dual orexin receptor antagonist, recently received approval from the US Food and Drug Administration to treat insomnia. In Experiment 1, rats self-administered cocaine under a progressive-ratio schedule of reinforcement and the effects of suvorexant on motivation to self-administer cocaine were measured...
April 17, 2017: Addiction Biology
https://www.readbyqxmd.com/read/28303403/hypocretin-orexin-and-plastic-adaptations-associated-with-drug-abuse
#12
Corey Baimel, Stephanie L Borgland
Dopamine neurons in the ventral tegmental area (VTA) are a critical part of the neural circuits that underlie reward learning and motivation. Dopamine neurons send dense projections throughout the brain and recent observations suggest that both the intrinsic properties and the functional output of dopamine neurons are dependent on projection target and are subject to neuromodulatory influences. Lateral hypothalamic hypocretin (also termed orexin) neurons project to the VTA and contain both hypocretin and dynorphin peptides in the same dense core vesicles suggesting they may be co-released...
2017: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/28296947/the-dual-orexin-receptor-antagonist-tcs1102-does-not-affect-reinstatement-of-nicotine-seeking
#13
Shaun Yon-Seng Khoo, Gavan P McNally, Kelly J Clemens
The orexin/hypocretin system is important for appetitive motivation towards multiple drugs of abuse, including nicotine. Both OX1 and OX2 receptors individually have been shown to influence nicotine self-administration and reinstatement. Due to the increasing clinical use of dual orexin receptor antagonists in the treatment of disorders such as insomnia, we examined whether a dual orexin receptor antagonist may also be effective in reducing nicotine seeking. We tested the effect of intracerebroventricular (i...
2017: PloS One
https://www.readbyqxmd.com/read/28250055/mapping-the-hypocretin-orexin-neuronal-system-an-unexpectedly-productive-journey
#14
Christelle Peyron, Thomas S Kilduff
Early in 1998, we (de Lecea et al., 1998) and others (Sakurai et al., 1998) described the same hypothalamic neuropeptides, respectively called the hypocretins or orexins, which were discovered using two different approaches. In December of that year, we published the subject of this commentary in the Journal of Neuroscience: a highly detailed anatomical description of the extensive axonal projections of the hypocretin/orexin neurons. Although the function of this system was unknown at the time, a large body of literature today attests that the hypocretin/orexin neuropeptides play important roles in multiple physiological functions, particularly in sleep/wake regulation...
March 1, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28212941/injections-of-the-of-the-%C3%AE-1-adrenoceptor-antagonist-prazosin-into-the-median-raphe-nucleus-increase-food-intake-and-fos-expression-in-orexin-neurons-of-free-feeding-rats
#15
Eduardo Simão da Silva, Rafael Appel Flores, Anderson Savaris Ribas, Ana Paula Taschetto, Moacir Serralvo Faria, Leandro Bueno Lima, Martin Metzger, José Donato, Marta Aparecida Paschoalini
Previously, we showed that the blockade of α1-adrenoreceptors in the median raphe nucleus (MnR) increased food intake in free-feeding rats, indicating that adrenergic mechanisms in the MnR participate in the regulation of food intake. However, the impact of such a pharmacological manipulation on other neural circuits related to food intake remains unknown. In the current study, we sought to identify forebrain regions which are responsive to α1-adrenergic receptor blockade and presumably involved in the modulation of the feeding response...
May 1, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28178514/projection-target-defined-effects-of-orexin-and-dynorphin-on-vta-dopamine-neurons
#16
Corey Baimel, Benjamin K Lau, Min Qiao, Stephanie L Borgland
Circuit-specific signaling of ventral tegmental area (VTA) dopamine neurons drives different aspects of motivated behavior, but the neuromodulatory control of these circuits is unclear. We tested the actions of co-expressed lateral hypothalamic peptides, orexin A (oxA) and dynorphin (dyn), on projection-target-defined dopamine neurons in mice. We determined that VTA dopamine neurons that project to the nucleus accumbens lateral shell (lAcbSh), medial shell (mAcbSh), and basolateral amygdala (BLA) are largely non-overlapping cell populations with different electrophysiological properties...
February 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28025575/patterned-feeding-induces-neuroendocrine-behavioral-and-genetic-changes-that-promote-palatable-food-intake
#17
S Sirohi, A Van Cleef, J F Davis
BACKGROUND: Selection of a healthy diet is the cornerstone for treating obesity and metabolic disease. Unfortunately, the majority of diets fail leading to weight regain and in some cases, pathological feeding behavior. We hypothesize that alternating bouts of caloric overconsumption and caloric restriction, behavioral manifestations of dieting induce neuroendocrine, behavioral and genetic changes that promote future bouts of palatable food intake. METHODS: To test this hypothesis, we subjected male Long-Evans rats to a high-fat diet (HFD) feeding paradigm that induced a pattern of caloric overconsumption and caloric restriction...
January 31, 2017: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/28012090/a-decade-of-orexin-hypocretin-and-addiction-where-are-we-now
#18
REVIEW
Morgan H James, Stephen V Mahler, David E Moorman, Gary Aston-Jones
One decade ago, our laboratory provided the first direct evidence linking orexin/hypocretin signaling with drug seeking by showing that activation of these neurons promotes conditioned morphine-seeking behavior. In the years since, contributions from many investigators have revealed roles for orexins in addiction for all drugs of abuse tested, but only under select circumstances. We recently proposed that orexins play a fundamentally unified role in coordinating "motivational activation" under numerous behavioral conditions, and here we unpack this hypothesis as it applies to drug addiction...
2017: Current Topics in Behavioral Neurosciences
https://www.readbyqxmd.com/read/27997037/descending-projections-from-the-basal-forebrain-to-the-orexin-neurons-in-mice
#19
Lindsay J Agostinelli, Loris L Ferrari, Carrie E Mahoney, Takatoshi Mochizuki, Bradford B Lowell, Elda Arrigoni, Thomas E Scammell
The orexin (hypocretin) neurons play an essential role in promoting arousal, and loss of the orexin neurons results in narcolepsy, a condition characterized by chronic sleepiness and cataplexy. The orexin neurons excite wake-promoting neurons in the basal forebrain (BF), and a reciprocal projection from the BF back to the orexin neurons may help promote arousal and motivation. The BF contains at least three different cell types (cholinergic, glutamatergic, and γ-aminobutyric acid (GABA)ergic neurons) across its different regions (medial septum, diagonal band, magnocellular preoptic area, and substantia innominata)...
May 1, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/27909992/roles-for-orexin-hypocretin-in-the-control-of-energy-balance-and-metabolism
#20
REVIEW
Paulette B Goforth, Martin G Myers
The neuropeptide hypocretin is also commonly referred to as orexin, since its orexigenic action was recognized early. Orexin/hypocretin (OX) neurons project widely throughout the brain and the physiologic and behavioral functions of OX are much more complex than initially conceived based upon the stimulation of feeding. OX most notably controls functions relevant to attention, alertness, and motivation. OX also plays multiple crucial roles in the control of food intake, metabolism, and overall energy balance in mammals...
2017: Current Topics in Behavioral Neurosciences
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