Exploring the association between hypocretin-1 levels and bone mineral content in patients with narcolepsy: A cross-sectional study.

INTRODUCTION: Recent studies suggest the existence of a physiologic basis for bone rarefaction and increased risk for fractures. This study aimed to address anthropometric differences between patients with narcolepsy type 1 (NT1) and type 2 (NT2) and discrepancies in bone mineral content (BMC) as a function of hypocretin-1 (Hcrt-1) measured in cerebrospinal fluid (CSF). METHODS: We have evaluated 31 adult patients (aged 18-65 years) with NT1 and 18 patients with NT2, comparing the groups in terms of anthropometric variables - body mass index (BMI) and waist-to-hip ratio (WHR) - and percentage of bone mineral content (%BMC), measured by bioelectrical impedance analysis (BIA). Statistical analysis assessed the effects of Hcrt-1 levels on CSF, dietary intake, and medication use over these variables. Statistical significance was achieved with a confidence interval of 95 % and p < 0.05. RESULTS: Patients with NT1 presented with higher BMI (32.04 ± 6.95 vs. 25.38 ± 4.26 kg/m2; p < 0.01) and WHR (0.89 ± 0.09 vs. 0.83 ± 0.09; p = 0.02) compared to NT2, in detriment of %BMC, which was lower for NT1 (4.1 ± 1.02 vs. 4.89 ± 0.59; p < 0.01). Hcrt-1 in CSF showed a positive correlation with %BMC (r = +0.48, p < 0.01) and a negative correlation with anthropometric features (BMI: r = -0.54, p < 0.01; WHR: r = -0.37, p = 0.01). There was a correlation between WHR and diary caloric intake (r = +0.42, p < 0.01). CONCLUSION: The evaluation of patients with narcolepsy presupposes a syndromic approach comprising symptoms that go far beyond excessive daytime sleepiness. The integrated follow-up, including nutritional profile and anthropometric features, should add value in reducing morbidity in this population.

Hypocretins, sleep, and maternal behavior.

The postpartum period is a demanding time during which mothers experience numerous physiological adaptations that enable them to care for their offspring while maintaining their wellbeing. Hypocretins, also known as orexins, are neuropeptides synthesized by hypothalamic neurons that play a fundamental role in several functions, including the promotion of wakefulness and motivated behaviors, such as maternal care. In this regard, several findings suggest that the activity of the hypocretinergic system increases in the early postpartum period and begins to decline as weaning approaches. In particular, hypocretins within the medial preoptic area, a crucial region during this period, modulate both maternal behavior and sleep. Although further studies are necessary to obtain a comprehensive understanding of the role of hypocretins in lactating females, current research suggests that this system participates in promoting active components of maternal behavior and regulating wakefulness and sleep adjustments during the postpartum period, potentially leading to increased wakefulness during this stage. These adaptive adjustments enable the mother to cope with the continuously changing demands of the pups.

Electrophysiological characterization of medial preoptic neurons in lactating rats and its modulation by hypocretin-1.

The medial preoptic area (mPOA) undergoes through neuroanatomical changes across the postpartum period, during which its neurons play a critical role in the regulation of maternal behavior. In addition, this area is also crucial for sleep-wake regulation. We have previously shown that hypocretins (HCRT) within the mPOA facilitate active maternal behaviors in postpartum rats, while the blockade of endogenous HCRT in this area promotes nursing and sleep. To explore the mechanisms behind these HCRT actions, we aimed to evaluate the effects of juxta-cellular HCRT-1 administration on mPOA neurons in urethane-anesthetized postpartum and virgin female rats. We recorded mPOA single units and the electroencephalogram (EEG) and applied HCRT-1 juxta-cellular by pressure pulses. Our main results show that the electrophysiological characteristics of the mPOA neurons and their relationship with the EEG of postpartum rats did not differ from virgin rats. Additionally, neurons that respond to HCRT-1 had a slower firing rate than those that did not. In addition, administration of HCRT increased the activity in one group of neurons while decreasing it in another, both in postpartum and virgin rats. This study suggests that the mechanisms by which HCRT modulate functions controlled by the mPOA involve different cell populations.

Brain site-specific regulation of hedonic intake by orexin and DYN peptides: role of the PVN and obesity.

The orexin peptides promote hedonic intake and other reward behaviors through different brain sites. The opioid dynorphin peptides are co-released with orexin peptides but block their effects on reward in the ventral tegmental area (VTA). We previously showed that in the paraventricular hypothalamic nucleus (PVN), dynorphin and not orexin peptides enhance hedonic intake, suggesting they have brain-site-specific effects. Obesity alters the expression of orexin and dynorphin receptors, but whether their expression across different brain sites is important to hedonic intake is unclear. We hypothesized that hedonic intake is regulated by orexin and dynorphin peptides in PVN and that hedonic intake in obesity correlates with expression of their receptors. Here we show that in mice, injection of DYN-A1-13 (an opioid dynorphin peptide) in the PVN enhanced hedonic intake, whereas in the VTA, injection of OXA (orexin-A, an orexin peptide) enhanced hedonic intake. In PVN, OXA blunted the increase in hedonic intake caused by DYN-A1-13. In PVN, injection of norBNI (opioid receptor antagonist) reduced hedonic intake but a subsequent OXA injection failed to increase hedonic intake, suggesting that OXA activity in PVN is not influenced by endogenous opioid activity. In the PVN, DYN-A1-13 increased the intake of the less-preferred food in a two-food choice task. In obese mice fed a cafeteria diet, orexin 1 receptor mRNA across brain sites involved in hedonic intake correlated with fat preference but not caloric intake. Together, these data support that orexin and dynorphin peptides regulate hedonic intake in an opposing manner with brain-site-specific effects.

Role of Hypocretin in the Medial Preoptic Area in the Regulation of Sleep, Maternal Behavior and Body Temperature of Lactating Rats.

Hypocretins (HCRT), also known as orexins, includes two neuroexcitatory peptides, HCRT-1 and HCRT-2 (orexin A y B, respectively), synthesized by neurons located in the postero-lateral hypothalamus, whose projections and receptors are widely distributed throughout the brain, including the medial preoptic area (mPOA). HCRT have been associated with a wide range of physiological functions including sleep-wake cycle, maternal behavior and body temperature, all regulated by the mPOA. Previously, we showed that HCRT in the mPOA facilitates certain active maternal behaviors, while the blockade of HCRT-R1 increases the time spent in nursing. As mother rats mainly sleep while they nurse, we hypothesize that HCRT in the mPOA of lactating rats reduce sleep and nursing, while intra-mPOA administration of a dual orexin receptor antagonist (DORA) would cause the opposite effect. Therefore, the aim of this study was to determine the role of HCRT within the mPOA, in the regulation and integration of the sleep-wake cycle, maternal behavior and body temperature of lactating rats. For that purpose, we assessed the sleep-wake states, maternal behavior and body temperature of lactating rats following microinjections of HCRT-1 (100 and 200 µM) and DORA (5 mM) into the mPOA. As expected, our data show that HCRT-1 in mPOA promote wakefulness and a slightly increase in body temperature, whereas DORA increases both NREM and REM sleep together with an increment of nursing and milk ejection. Taken together, our results strongly suggest that the endogenous reduction of HCRT within the mPOA contribute to the promotion of sleep, milk ejection and nursing behavior in lactating rats.

Nandrolone decanoate and resistance exercise affect body composition and energy metabolism.

Our aim was to evaluate the independent and associated effects of nandrolone decanoate (DECA) and resistance exercise (REx) on central and peripheral hormones and neuropeptides related to energy balance in male rats. The experimental protocol was performed for eight weeks and comprised four groups: control (C) - exposed to vehicle 3x/wk; trained (T) - REx 5x/wk and vehicle 3x/wk; decanoate (D) - exposed to DECA (5 mg/kg) 3x/wk, and REx with DECA (TD) - submitted to REx 5x/wk and DECA (5 mg/kg) 3x/wk. Cross-sectional area analysis of the gastrocnemius muscle was higher in the T and TD groups compared to the C group. Biometrical analyses showed a decrease in body weight only in the TD compared to the C group, however, a reduction in total fat mass was observed in both the T and TD when compared to the C group. In respect of hypothalamic mRNA expression, there was an increase in prepro-orexin in the T compared to the C group. In mesenteric fat there was a decrease in leptin expression in the T and TD compared to the C group. Plasma evaluations showed reduced leptin concentrations in D, T and TD compared to C, and an increase in orexin-A in the D group compared to the C and T groups. Our data showed that REx was related to central and peripheral changes in energy metabolism, while DECA changed only peripheral components. REx associated with DECA promoted peripheral changes in energy metabolism and decreased body and fat weights.

Health-related quality of life in patients with narcolepsy types 1 and 2 from a Sleep Center in Brazil / Qualidade de vida relacionada à saúde em pacientes com narcolepsia tipos 1 e 2 de um Centro de Sono no Brasil

ABSTRACT Introduction: Narcolepsy patients have higher prevalence of comorbidities, such as obesity, depression, and pain. Narcolepsy symptoms and concomitant medical conditions can impact the daily activities of patients. The objective of this study is to describe the quality of life in a sample of patients with narcolepsy, and the influence of the nutritional status in health domains. Methods: At Unifesp, two groups of 33 patients (narcolepsy types 1 and 2 meeting 2014 criteria, concerning hypocretin-1) and 33 controls without sleepiness, matched by age and sex, filled out the SF-36. Results: Narcolepsy groups, regardless of their nutritional status, had significantly lower scores in all domains, compared to controls, mainly in Role-physical, Role-emotional, and Energy/Fatigue. Role-physical score was lower in type 1 than in type 2 and controls (37.8±1.0 vs. 50.0±1.2 vs. 85.6±1.6; p<0.0001). Obese with type 2 narcolepsy scored lower than type 1 in physical scales. Conclusion: In a Sleep Center in São Paulo, Brazil, physical and mental health were impaired in narcolepsy types 1 and 2. The first report of the poor health status in Brazilians with narcolepsy type 2 suggests that obesity negatively affects physical domains.

RESUMO Introdução: Pacientes com narcolepsia têm maior prevalência de comorbidades, como obesidade, depressão e dor. Sintomas de narcolepsia e condições médicas concomitantes podem afetar as atividades diárias dos pacientes. O objetivo deste estudo é escrever a qualidade de vida em uma amostra de pacientes com narcolepsia e a influência do estado nutricional nos domínios de saúde. Métodos: Na Unifesp, dois grupos de 33 pacientes (narcolepsia tipos 1 e 2 compatível com os critérios de 2014, em relação a hipocretina-1) e 33 controles sem sonolência, pareados por idade e sexo, preencheram o SF-36. Resultados: Os grupos de narcolepsia, independentemente do estado nutricional, apresentaram pontuações significantemente menores em todos os domínios, comparados aos controles, principalmente nos quesitos físico, emocional e energia/fadiga. A pontuação do critério físico foi menor no tipo 1 do que no tipo 2 e nos controles (37,8±1,0 vs. 50,0±1,2 vs. 85,6±1,6; p<0,0001). Obesos com tipo 2 tiveram pontuação menor do que os com tipo 1 nas escalas físicas. Conclusão: Em um Centro de Sono de São Paulo, Brasil, as saúdes física e mental estavam comprometidas na narcolepsia tipos 1 e 2. O primeiro relato de estado de saúde ruim em brasileiros com narcolepsia tipo 2 sugere que a obesidade afeta negativamente os domínios físicos.

Depletion of hypothalamic hypocretin/orexin neurons correlates with impaired memory in a Parkinson's disease animal model.

Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and affects multiple neurotransmission systems such as hypocretin/orexin (HO) release and can lead to cognitive and memory deficits. The HO neurons located in lateral hypothalamus/perifornical area (LH/PeF) are involved with consolidation and memory processes. Here we verified the involvement of HO deficit in learning and memory process in an animal model of PD induced by bilateral intra-striatal injections of 6-hydroxydopamine (6-OHDA). The present study performed a working memory test by object recognition task and spatial memory test using the Morris water maze in control and PD-induced animals after depletion of HO neurons. In addition, our results indicate that HO system in degenerative disorders such as PD may modulate the declarative and spatial memory (assessed by object recognition and Morris water maze tests, respectively). A significant reduction of HO neurons in the LH/PeF and HO degeneration process in the hippocampus (CA1 and dentate gyrus areas) were noticed. Our data suggest that the HO system degeneration could be associated to memory dysfunction in PD.

Cannabidiol Partially Blocks the Excessive Sleepiness in Hypocretindeficient Rats: Preliminary Data.

BACKGROUND: Excessive daytime sleepiness and cataplexy are among the symptoms of narcolepsy, a sleep disorder caused by the loss of hypocretin/orexin (HCRT/OX) neurons placed into the Hypothalamus (LH). Several treatments for managing narcolepsy include diverse drugs to induce alertness, such as antidepressants, amphetamine, or modafinil, etc. Recent evidence has shown that cannabidiol (CBD), a non-psychotropic derived from Cannabis sativa, shows positive therapeutic effects in neurodegenerative disorders, including Parkinson´s disease. Furthermore, CBD provokes alertness and enhances wake-related neurochemicals in laboratory animals. Thus, it is plausible to hypothesize that excessive somnolence observed in narcolepsy might be blocked by CBD. OBJECTIVE: Here, we determined whether the systemic injection of CBD (5mg/kg, i.p.) would block the excessive sleepiness in a narcoleptic model. METHODS: To test this idea, the neurotoxin hypocretin-2-saporin (HCRT2/SAP) was bilaterally injected into the LH of rats to eliminate HCRT leading to the establishment of narcoleptic-like behavior. Since excessive somnolence in HCRT2/SAP lesioned rats has been observed during the lights-off period, CBD was administered at the beginning of the dark phase. RESULTS: Hourly analysis of sleep data showed that CBD blocked the sleepiness during the lights-off period across 7h post-injection in lesioned rats. CONCLUSION: Taking together, these preliminary findings suggest that CBD might prevent sleepiness in narcolepsy.

Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra compacta (SNpc) and the only risk factor is aging. We showed that in 6-hydroxydopamine (6-OHDA)-model of PD there is a reduction in the neuronal profile within the brainstem ventral respiratory column with a decrease in the hypercapnic ventilatory response. Here we tested the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing in a 6-OHDA PD model. In this model of PD, there is a reduction in the total number of orexinergic neurons and in the number of orexinergic neurons that project to the RTN, without changing the number of CO2-activated orexinergic neurons during the dark phase. The ventilation at rest and in response to hypercapnia (7% CO2) was assessed in animals that received 6-OHDA or vehicle injections into the striatum and saporin anti-Orexin-B or IgG saporin into the LH/PeF during the sleep and awake states. The experiments showed a reduction of respiratory frequency (fR) at rest during the light phase in PD animals only during sleep. During the dark phase, there was an impaired fR response to hypercapnia in PD animals with depletion of orexinergic neurons in awake and sleeping rats. In conclusion, the degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.

The weaning period promotes alterations in the orexin neuronal population of rats in a suckling-dependent manner.

The orexin-immunoreactive neurons are part of an important arousal-promoting hypothalamic population. Several groups have investigated these neurons during the lactation period, when numerous physiological alterations occur in the dam's body to cope with the newly acquired metabolic needs of the litter. Although those studies have probed this population during the early and intermediate stages of lactation, few works have examined its response to weaning, including the cessation of the tactile suckling stimulus as the litter stops nursing. Using double immunohistochemistry for orexin and FOS combined with three-dimensional reconstruction techniques, we investigated orexin-synthesizing neurons and their activation at different times during weaning, in addition to the role played by the suckling stimulus. We report here that weaning promoted a decline in the anterior population of orexin-immunoreactive neurons and decreased the number of double orexin-FOS neurons labeled in the central dorsomedial hypothalamus, in addition to reducing the overall number of FOS-immunoreactive cells in the whole tuberal hypothalamus. Disruption of the suckling stimulus from the pups impaired the decrease in the number of anteriorly located orexin-immunoreactive neurons, attenuated the activation of orexin-synthesizing cells in the dorsomedial hypothalamus and reduced the number of FOS-immunoreactive neurons across the tuberal hypothalamus. When taken together, our data suggest that the weaning period is necessary to restore neurochemical pathways altered during the lactation period and that the suckling stimulus plays a significant role in this process.

Depletion of Hypocretin/Orexin Neurons Increases Cell Proliferation in the Adult Subventricular Zone.

BACKGROUND & OBJECTIVE: Adult neurogenesis, a specific form of brain plasticity in mammals that occurs in the subventricular zone, is subject to complex regulation. Hypocretin/orexin neurons are implicated in the regulation of sleep and arousal states, among other functions. Here we report for the first time the presence of orexinergic projections within the adult rat subventricular zone. Post-mortem retrograde tracing combined with immunofluorescence indicated orexinergic projections toward the subventricular zone. To establish the relationship between the depletion of orexin neurons and the number of proliferating cells in the subventricular zone, we labeled mitotic cells. Histological analysis revealed proliferating cells to be in close contact with orexinergic fibers. Neurotoxinlesioning of orexin neurons in the lateral hypothalamus significantly activated precursor cell proliferation in the subventricular zone. Furthermore, cell proliferation in both normal and lesioned animals failed to reveal newly born orexin neurons in the lateral hypothalamus. CONCLUSION: Based on these findings, we suggest that the adult subventricular zone is affected by orexinergic signaling, the functional implication of which must be further elucidated.

Basal Forebrain Cholinergic System and Memory.

Basal forebrain cholinergic neurons constitute a way station for many ascending and descending pathways. These cholinergic neurons have a role in eliciting cortical activation and arousal. It is well established that they are mainly involved in cognitive processes requiring increased levels of arousal, attentive states and/or cortical activation with desynchronized activity in the EEG. These cholinergic neurons are modulated by several afferents of different neurotransmitter systems. Of particular importance within the cortical targets of basal forebrain neurons is the hippocampal cortex. The septohippocampal pathway is a bidirectional pathway constituting the main septal efferent system, which is widely known to be implicated in every memory process investigated. The present work aims to review the main neurotransmitter systems involved in modulating cognitive processes related to learning and memory through modulation of basal forebrain neurons.

Subchronical treatment with Fluoxetine modifies the activity of the MCHergic and hypocretinergic systems. Evidences from peptide CSF concentration and gene expression.

In the postero-lateral hypothalamus are located two neuronal systems that utilize the neuropeptides melanin-concentrating hormone (MCH) and hypocretins (also called orexins) as neuromodulators. These systems have reciprocal connections between them, and project throughout the central nervous system. MCH has been involved in the generation of sleep, mainly REM sleep, while hypocretins have a critical role in the generation of wakefulness. MCHergic activity is also involved in the pathophysiology of major depressive disorder (MD). In this regards, intracerebral administration of MCH promotes pro-depressive behaviors (i.e., immobility in the forced swimming test) and REM sleep hypersomnia, which is an important trait of depression. Furthermore, the antagonism of the MCHR-1 receptor has a reliable antidepressant effect, suggesting that MCH is a pro-depressive factor. Hypocretins have been also involved in mood regulation; however, their role in depression is still on debate. Taking these data into account, we explored whether systemic subchronical treatment with Fluoxetine (FLX), a serotonergic antidepressant, modifies the concentration of MCH in the cerebrospinal fluid (CSF), as well as the preproMCH mRNA expression. We also evaluated the hypocretinergic system by quantifying the hypocretin-levels in the CSF and the preprohypocretin mRNA expression. Compared to control, FLX increased the levels of preprohypocretin mRNA without affecting the hypocretin-1 CSF levels. On the contrary, FLX significantly decreased the MCH CSF concentration without affecting the preproMCH gene expression. This result is in agreement with the fact that MCH serum level diminishes during the antidepressant treatment in MD, and supports the hypothesis that an increase in the MCHergic activity could have pro-depressive consequences.

Hypocretinergic system in the medial preoptic area promotes maternal behavior in lactating rats.

Hypocretin-1 and 2 (HCRT-1 and HCRT-2, respectively) are neuropeptides synthesized by neurons located in the postero-lateral hypothalamus, whose projections are widely distributed throughout the brain. The hypocretinergic (HCRTergic) system has been associated with the generation and maintenance of wakefulness, as well as with the promotion of motivated behaviors. In lactating rats, intra-cerebroventricular HCRT-1 administration stimulates maternal behavior, whilst lactation per se increases the expression of HCRT type 1 receptor (HCRT-R1). Due to the fact that HCRTergic receptors are expressed in the medial preoptic area (mPOA), a region critically involved in maternal behavior, we hypothesize that HCRT-1 promotes maternal behavior acting on this region. In order to evaluate this hypothesis, we assessed the maternal behavior of lactating rats following microinjections of HCRT-1 (10 or 100µM) and the selective HCRT-R1 antagonist SB-334867 (250µM) into the mPOA, during the first and second postpartum weeks. While intra-mPOA microinjections of HCRT-1 (100µM) increased corporal pup licking during the second postpartum week, the blockade of HCRT-R1 significantly decreased active components of maternal behavior, such as retrievals, corporal and ano-genital lickings, and increased the time spent in nursing postures in both postpartum periods. We conclude that HCRTergic system in the mPOA may stimulate maternal behavior, suggesting that endogenous HCRT-1 is necessary for the natural display of this behavior.

Orexin in the toad Rhinella schneideri: The location of orexinergic neurons and the role of orexin in ventilatory responses to hypercarbia and hypoxia.

Recent reports have suggested that orexins, also known as hypocretins, play an important role in the modulation of respiratory control in mammals, but there are no data available describing the role of the orexinergic system in the peripheral and central chemoreception of non-mammalian vertebrates. Therefore, the present study was designed to examine the localization of orexin-immunoreactive neurons in the brain of toads (Rhinella schneideri) and to investigate the contribution of orexin receptor-1 (OX1R) to the hypoxic and hypercarbic ventilatory responses of these animals during light and dark phases. Our results demonstrated that the orexinergic neurons of R. schneideri are located in the suprachiasmatic nucleus of the diencephalon. Additionally, the intracerebroventricular injection of SB-334867 (OX1R selective antagonist) attenuated the ventilatory response to hypercarbia during the dark phase by acting on tidal volume and breathing frequency, while during the light phase, SB-334867 attenuated the ventilatory response to hypoxia by acting on tidal volume only. We conclude that in the toad R. schneideri, orexinergic neurons are located in the suprachiasmatic nucleus and that OX1R contributes to hypercarbic and hypoxic chemoreflexes.

Progressive Loss of the Orexin Neurons Reveals Dual Effects on Wakefulness.

STUDY OBJECTIVES: Narcolepsy is caused by loss of the orexin (also known as hypocretin) neurons. In addition to the orexin peptides, these neurons release additional neurotransmitters, which may produce complex effects on sleep/wake behavior. Currently, it remains unknown whether the orexin neurons promote the initiation as well as the maintenance of wakefulness, and whether the orexin neurons influence initiation or maintenance of sleep. To determine the effects of the orexin neurons on the dynamics of sleep/wake behavior, we analyzed sleep/wake architecture in a novel mouse model of acute orexin neuron loss. METHODS: We used survival analysis and other statistical methods to analyze sleep/wake architecture in orexin-tTA ; TetO diphtheria toxin A mice at different stages of orexin neuron degeneration. RESULTS: Progressive loss of the orexin neurons dramatically reduced survival of long wake bouts, but it also improved survival of brief wake bouts. In addition, with loss of the orexin neurons, mice were more likely to wake during the first 30 sec of nonrapid eye movement sleep and then less likely to return to sleep during the first 60 sec of wakefulness. CONCLUSIONS: These findings help explain the sleepiness and fragmented sleep that are characteristic of narcolepsy. Orexin neuron loss impairs survival of long wake bouts resulting in poor maintenance of wakefulness, but this neuronal loss also fragments sleep by increasing the risk of awakening at the beginning of sleep and then reducing the likelihood of quickly returning to sleep.

Role of the non-opioid dynorphin peptide des-Tyr-dynorphin (DYN-A(2-17)) in food intake and physical activity, and its interaction with orexin-A.

Food intake and physical activity are regulated by multiple neuropeptides, including orexin and dynorphin (DYN). Orexin-A (OXA) is one of two orexin peptides with robust roles in regulation of food intake and spontaneous physical activity (SPA). DYN collectively refers to several peptides, some of which act through opioid receptors (opioid DYN) and some whose biological effects are not mediated by opioid receptors (non-opioid DYN). While opioid DYN is known to increase food intake, the effects of non-opioid DYN peptides on food intake and SPA are unknown. Neurons that co-express and release OXA and DYN are located within the lateral hypothalamus. Limited evidence suggests that OXA and opioid DYN peptides can interact to modulate some aspects of behaviors classically related to orexin peptide function. The paraventricular hypothalamic nucleus (PVN) is a brain area where OXA and DYN peptides might interact to modulate food intake and SPA. We demonstrate that injection of des-Tyr-dynorphin (DYN-A(2-17), a non opioid DYN peptide) into the PVN increases food intake and SPA in adult mice. Co-injection of DYN-A(2-17) and OXA in the PVN further increases food intake compared to DYN-A(2-17) or OXA alone. This is the first report describing the effects of non-opioid DYN-A(2-17) on food intake and SPA, and suggests that DYN-A(2-17) interacts with OXA in the PVN to modulate food intake. Our data suggest a novel function for non-opioid DYN-A(2-17) on food intake, supporting the concept that some behavioral effects of the orexin neurons result from combined actions of the orexin and DYN peptides.

The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship.

Orexins (hypocretins) are neuropeptides synthesized in neurons located in the lateral (LH), perifornical, and dorsomedial (DMH) hypothalamus. These neurons innervate many regions in the brain and modulate multiple other neurotransmitter systems. As a result of these extensive projections and interactions orexins are involved in numerous functions, such as feeding behavior, neuroendocrine regulation, the sleep-wake cycle, and reward-seeking. This review will summarize the literature to date which has evaluated a role of orexins in the behavioral effects of alcohol, with a focus on understanding the importance of this peptide and its potential as a clinical therapeutic target for alcohol use disorders.

Symptomatic narcolepsy in a dog with hypophisary macroadenoma / Narcolepsia sintomática em um cão com macroadenoma hipofisário

Background: Narcolepsy is a neurologic sleep disorder, in humans characterized by excessive and recurrent daytime sleepiness, rapid eye movement in the beginning of the sleep, in association with hypnagogic hallucinations and sleep paralysis, with or without cataplexy. In dogs, the characteristic symptom is cataplexy and narcolepsy exists in two forms, one genetic and one acquired. This article describes one case of narcolepsy as a symptom due to an adenohypophysis tumor.Case: Dog presenting progressive signs of appetite loss, incoordination and constant falling. At clinical evaluation, the dog presented cachexia, hipocolored mucosae and compulsively walking in circles to the right, the four limbs collapsed from physical exhaustion, remaining in a narcoleptic state. Complementary exams, like x-ray, ultrasonography, hemogram and biochemical examination did not show signifi cant alterations. The patient was hospitalized for recovery of general status and corticoid treatment was initiated, but after two days it died. Necropsy reported that the cause of death was 180º gastric torsion and adrenals presented diffuse and marked enlargement of the cortical layer, 1.5 cm diameter neoplasia at the base of the brain and 0.5 cm diameter cavitation in the cerebral parenchyma. In the microscopic examination, adrenals were hyperplastic at the cortical region and there was round cell prolifera

Background: Narcolepsy is a neurologic sleep disorder, in humans characterized by excessive and recurrent daytime sleepiness, rapid eye movement in the beginning of the sleep, in association with hypnagogic hallucinations and sleep paralysis, with or without cataplexy. In dogs, the characteristic symptom is cataplexy and narcolepsy exists in two forms, one genetic and one acquired. This article describes one case of narcolepsy as a symptom due to an adenohypophysis tumor.Case: Dog presenting progressive signs of appetite loss, incoordination and constant falling. At clinical evaluation, the dog presented cachexia, hipocolored mucosae and compulsively walking in circles to the right, the four limbs collapsed from physical exhaustion, remaining in a narcoleptic state. Complementary exams, like x-ray, ultrasonography, hemogram and biochemical examination did not show signifi cant alterations. The patient was hospitalized for recovery of general status and corticoid treatment was initiated, but after two days it died. Necropsy reported that the cause of death was 180º gastric torsion and adrenals presented diffuse and marked enlargement of the cortical layer, 1.5 cm diameter neoplasia at the base of the brain and 0.5 cm diameter cavitation in the cerebral parenchyma. In the microscopic examination, adrenals were hyperplastic at the cortical region and there was round cell prolifera