The orexinergic system and its receptors are involved in many physiological processes. Their functions in energy homeostasis, arousal, cognition, stress processing, endocrine functions, and pain modulation have been investigated. Many studies have shown that the orexinergic system cooperates with the dopaminergic system in the addiction process. Emerging evidence suggests that the orexinergic system can be effective in the induction of drug dependence and tolerance. Therefore, several researches have been conducted on the effect of orexin receptor (OXR) antagonists on reducing tolerance and dependence caused by drug abuse. Due to the significant growth of the studies on the orexinergic system, the current literature was conducted to collect the findings of previous studies on orexin and its receptors in the induction of drug addiction. In addition, cellular and molecular mechanisms of the possible role of orexin in drug tolerance and dependence are discussed. The findings indicate that the administration of OXR antagonists reduces drug dependence. OXR blockers seem to counteract the addictive effects of drugs through multiple mechanisms, such as preventing neuronal adaptation. This review proposes the potential clinical use of OXR antagonists in the treatment of drug dependence.

Introduction: Premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS), is a serious health disorder that affects patient moods. It is caused by cyclic psychological symptoms and its pathogenesis is still unclear. Abnormalities in the basolateral amygdala (BLA) orexin system, which are important causes of the development of depressive mood, have not been reported in PMDD, so exploring its intrinsic mechanisms is meaningful for enriching the pathomechanisms of PMDD. Methods: High performance liquid chromatography was used for the determination of the active ingredients of Jingqianshu granules. Developing a rat model of premenstrual depression using the forced swimming test (FST). The experiment consisted of two parts. In Part 1, the rats were divided into the control group, the model group, the model + Jingqianshu group, and the model + fluoxetine group. The FST, open field test, and elevated plus maze test, were used to assess the behavior of the rats as well as to evaluate the effect of drug intervention. Immunofluorescence and RT-qPCR were used to detect the expression of orexin and its receptors OX1R and OX2R genes and proteins. The expression of Toll-like receptor 4, nuclear factor kappa-B, tumor necrosis factor-α, interleukin 6, and interleukin-1β in the BLA brain region was detected by Western-Blot. In part 2, the rats were injected intracerebrally with orexin-A. Observe the behavioral activities of rats in the control group, model group, and model+orexin-A group. Immunofluorescence was used to detect microglia in the BLA area of rats, and the expression levels of the above inflammatory factors were detected by Western-Blot. Results: The five components of Jingqianshu granules are: paeoniflorin, erulic acid, liquiritin, hesperidin, and paeonol. During the estrous cycle, rats exhibited depressive-like behavior during the non-receptive phase of the behavioral test, which disappeared during the receptive phase. Immunofluorescence and RT-qPCR showed reduced gene and protein expression of orexin, OX1R, and OX2R in the BLA region of rats in the model group.WB showed elevated levels of inflammatory factors. All returned to control levels after drug treatment. In part 2, injection of orexin-A into the BLA brain region of model rats resulted in reduced immunoreactivity of microglia and decreased expression levels of inflammatory factors. Discussion: Jianqianshu granules can achieve the purpose of treating premenstrual depression by regulating orexin-mediated inflammatory factors, which provides a new idea for further research on the pathogenesis of PMDD. However, the current study is still preliminary and the pathogenesis of PMDD is complex. Therefore, more in-depth exploration is needed.

The fundamental conception of delirium is altered arousal. In addition, sleep-wake cycle isturbances including insomnia, excessive daytime napping, and disintegration of the xpected circadian patterns have been described as a characteristic component of delirium or decades, and demonstrated to be a core symptom domain of delirium. Although on-pharmacological interventions are successful to some extent, they have limitations due o various biological etiologies for delirium. Among pharmacological interventions, ntipsychotics seem to be effective, but they are not suitable for preventive use because f relatively frequent side-effects such as extrapyramidal symptoms. Recently, new type of rugs for insomnia have been focused with respect to delirium prevention. Recent eta-analyses show effectiveness of melatonin receptor agonists and orexin receptor ntagonists for delirium prevention, and real-world data support them.

Background: Insomnia is difficulty initiating or maintaining sleep for at least three nights a week or more and lasting for at least 3 months. One of the molecules that play a role in the circadian rhythm of arousal system is hypocretin/orexin. Orexin activates the p38-MAPK signaling pathway and increases phosphorylated ERK1/2 levels. Centella asiatica (CA) has a role in the signal work of the MAPK/ERK, Akt, and p38 path in many various diseases. Methods: The research method used is true laboratory experimental. The research approach used was randomized control group post-test only. Zebrafish embryos aged 0-7 dpf were used in this study. The treatment group consisted of 5 groups: normal, insomnia, insomnia + 2.5 μg/mL CA, insomnia + 5 μg/mL CA, and insomnia + 10 μg/mL CA. The locomotor motion of zebrafish larvae was observed using Basler cameras on days five-, six- and seven-day post fertilization (dpf), then analyzed by using Western Blot method. Results: The results proved that exposure to CA extract was able to reduce the expression of orexin (91963 ± 9129) and p38 (117425 ± 6398) as an arousal trigger in the sleep-wake cycle, with the most optimal concentration of CA 5 μg/mL. Exposure to CA extract was also able to reduce the expression of ERK (94795 ± 30830) and Akt (60113.5 ± 27833.5) with an optimum concentration of CA 2.5 μg/mL. Conclusion: Exposure to CA extract was able to improve the sleep activity of zebrafish larvae insomnia model by extending the total inactivity time ( cumulative duration) and shortening the duration of first sleep ( latency to first) in light and dark phases through inhibition of orexin, ERK, p38, and Akt.

Orexin/hypocretin terminals innervate the dorsal raphe nucleus (DRN), which projects to motor control areas important for spontaneous physical activity (SPA) and energy expenditure (EE). Orexin receptors are expressed in the DRN, and obesity-resistant (OR) rats show higher expression of these receptors in the DRN and elevated SPA/EE. We hypothesized that orexin-A in the DRN enhances SPA/EE and that DRN-GABA modulates the effect of orexin-A on SPA/EE. We manipulated orexin tone in the DRN either through direct injection of orexin-A or through the chemogenetic activation of lateral-hypothalamic (LH) orexin neurons. In the orexin neuron activation experiment, fifteen minutes prior to the chemogenetic activation of orexin neurons, the mice received either the GABA-agonist muscimol or antagonist bicuculline injected into the DRN, and SPA/EE was monitored for 24 h. In a separate experiment, orexin-A was injected into the DRN to study the direct effect of DRN orexin on SPA/EE. We found that the activation of orexin neurons elevates SPA/EE, and manipulation of GABA in the DRN does not alter the SPA response to orexin neuron activation. Similarly, intra-DRN orexin-A enhanced SPA and EE in the mice. These results suggest that orexin-A in the DRN facilitates negative energy balance by increasing physical activity-induced EE, and that modulation of DRN orexin-A is a potential strategy to promote SPA and EE.

We previously showed that orexin neurons are activated by hypoxia and facilitate the peripheral chemoreflex (PCR)-mediated hypoxic ventilatory response (HVR), mostly by promoting the respiratory frequency response. Orexin neurons project to the nucleus of the solitary tract (nTS) and the paraventricular nucleus of the hypothalamus (PVN). The PVN contributes significantly to the PCR and contains nTS-projecting corticotropin-releasing hormone (CRH) neurons. We hypothesized that in male rats, orexin neurons contribute to the PCR by activating nTS-projecting CRH neurons. We used neuronal tract tracing and immunohistochemistry (IHC) to quantify the degree that hypoxia activates PVN-projecting orexin neurons. We coupled this with orexin receptor (OxR) blockade with suvorexant (Suvo, 20 mg/kg, i.p.) to assess the degree that orexin facilitates the hypoxia-induced activation of CRH neurons in the PVN, including those projecting to the nTS. In separate groups of rats, we measured the PCR following systemic orexin 1 receptor (Ox1R) blockade (SB-334867; 1 mg/kg) and specific Ox1R knockdown in PVN. OxR blockade with Suvo reduced the number of nTS and PVN neurons activated by hypoxia, including those CRH neurons projecting to nTS. Hypoxia increased the number of activated PVN-projecting orexin neurons but had no effect on the number of activated nTS-projecting orexin neurons. Global Ox1R blockade and partial Ox1R knockdown in the PVN significantly reduced the PCR. Ox1R knockdown also reduced the number of activated PVN neurons and the number of activated tyrosine hydroxylase neurons in the nTS. Our findings suggest orexin facilitates the PCR via nTS-projecting CRH neurons expressing Ox1R.

Alzheimer\'s disease (AD) is the most common neurodegenerative condition and a form of dementia encountered in medical practice. Despite many proposed and attempted treatments, this disease remains a major puzzle in the public health systems worldwide. The initial part of this article provides an overview and illustration of the primary mechanisms responsible for neuronal damage in AD. Subsequently, it offers a critical evaluation of the most noteworthy studies on pharmacological therapy for AD and outlines recent advancements and novel approaches to managing this condition. Main properties, categorization, Food and Drug Administration (FDA) status, mechanisms of action, benefits, and common side effects of the classical and the most recently proposed pharmacological treatments for AD are described. The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab. Nutritional supplements such as alpha-tocopherol (vitamin E) and caprylidene are also revised. Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers. Antidiabetic and anti-neuroinflammation drugs recently proposed for AD treatment are discussed. The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia cells. Additional anti-inflammatory agents being currently tested in phase-2 clinical trials, such as atomoxetine (selective norepinephrine reuptake inhibitor), losartan (angiotensin 2 receptor agonist), genistein (anti-inflammatory isoflavone neuroprotective agent), trans-resveratrol (polyphenol antioxidant plant estrogen), and benfotiamine (synthetic thiamine precursor), were reviewed. Lastly, drugs targeting Alzheimer\'s-associated symptoms, such as brexpiprazole (serotonin dopamine activity modulator) and suvorexant (orexin receptor antagonist), respectively, used for agitation and insomnia in AD patients, are reviewed. As experimental investigations and clinical research progress, there is a possibility that a combination of newly tested medications and traditional ones may emerge as a promising treatment option for AD in the future.

Twenty-two years after their discovery, the hypocretins (Hcrts), also known as orexins, are two of the most studied peptidergic systems, involved in myriad physiological systems that range from sleep, arousal, motivation, homeostatic regulation, fear, anxiety and learning. A causal relationship between activity of Hcrt and arousal stability was established shortly after their discovery and have led to the development of a new class of drugs to treat insomnia. In this review we discuss the many faces of the Hcrt system and examine recent findings that implicate decreased Hcrt function in the pathogenesis of a number of neuropsychiatric conditions. We also discuss future therapeutic strategies to replace or enhance Hcrt function as a treatment option for these neuropsychiatric conditions.

UNASSIGNED: This case suggests using dual orexin receptor antagonists to treat alcohol use disorder and comorbid sleep disorders may be effective, commencing treatment in withdrawal and continuing it to prevent relapse.
UNASSIGNED: Effective medications for the treatment of alcohol use disorder are limited. This is partially due to the heterogenous nature of the symptomatology associated with alcohol use disorder and the abundance of presenting comorbidities. One common, and often overlooked, symptom that occurs during withdrawal of alcohol use is sleep disruption. Here, we report a case study of a participant with comorbid alcohol use disorder and insomnia. This participant was treated with a dual orexin receptor antagonist, suvorexant (Belsomra®), currently approved to treat insomnia. We demonstrate improvements in alcohol cravings, physical and psychological health, and sleep outcomes with treatment. These data support abundant preclinical and emerging clinical data in this space. The findings from this case report highlight the potential for suvorexant to treat comorbid alcohol use disorder and insomnia with fully powered, randomized controlled trials moving forward.

UNASSIGNED: Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO2) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO2 challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO2 reactivity predicts fear memory after extinction. We also examined whether CO2 reactivity predicts fear memory after retrieval-extinction.
UNASSIGNED: Male rats first underwent a CO2 challenge and fear conditioning and were assigned to receive either standard extinction (n = 28) or retrieval-extinction (n = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test.
UNASSIGNED: We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO2 reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree.
UNASSIGNED: CO2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.
Extinction learning underlies exposure therapy, a treatment for anxiety disorders. However, not everyone benefits from exposure therapy, highlighting the need in developing approaches that may help predict which individuals will respond. We tested whether extinction or an alternative treatment called retrieval-extinction would be more effective at reducing conditioned fear responses in rats and whether the response to a carbon dioxide (CO2) challenge would predict treatment response. We found that retrieval-extinction was more effective at reducing fear, and CO2 reactivity was better at predicting the response to extinction. These findings could help improve treatment strategies for anxiety disorders.