The Effect of Orexin Receptor Antagonism on Quinpirole-Induced Compulsive-Like Checking Behavior in Rats

Abounoori, Mahdi; Maddah, Mohammad Moein; Akbari, Esmaeil; Houshmand, Gholamreza; Ardeshiri, Motahareh Rouhi

doi:10.1007/s12640-020-00196-y

Cited by 15 publications

(13 citation statements)

References 29 publications

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“…8-OH-DPATinduced compulsive checking behavior in rats, whereby rats were unable to resist returning to a key locale during exploration of the open field [77]. This repetitive exploration was due to their compulsive behavior, in which they returned to the key locale again and again [55].…”

Section: Discussionmentioning

confidence: 99%

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Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder

et al. 2022

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Obsessive-compulsive disorder is a mental disorder characterized by repetitive, unwanted thoughts and behavior due to abnormal neuronal corticostriatal-thalamocortical pathway and other neurochemical changes. Purmorphamine is a smoothened-sonic-hedgehog agonist that has a protective effect against many neurological diseases due to its role in maintaining functional connectivity during CNS development and its anti-inflammatory and antioxidant properties. As part of our current research, we investigated the neuroprotective effects of PUR against behavioral and neurochemical changes in 8-hydroxy-2-(di-n-propylamino)-tetralin-induced obsessive-compulsive disorder in rats. Additionally, the effect of PUR was compared with the standard drug for OCD, i.e., fluvoxamine. The intra-dorsal raphe-nucleus injection of 8-OH-DPAT in rats for seven days significantly showed OCD-like repetitive and compulsive behavior along with increased oxidative stress, inflammation, apoptosis, as well as neurotransmitter imbalance. These alterations were dose-dependently attenuated by long-term purmorphamine treatment at 5 mg/kg and 10 mg/kg i.p. In this study, we assessed the level of various neurochemical parameters in different biological samples, including brain homogenate, blood plasma, and CSF, to check the drug’s effect centrally and peripherally. These effects were comparable to the standard oral treatment withfluvoxamine at 10 mg/kg. However, when fluvoxamine was given in combination with purmorphamine, there was a more significant restoration of these alterations than the individualtreatmentswithfluvoxamine and purmorphamine. All the above findings demonstrate that the neuroprotective effect of purmorphamine in OCD can be strong evidence for developing a new therapeutic target for treating and managing OCD.

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Section: Discussionmentioning

confidence: 99%

“…The amount of MDA wasmeasured by a spectrophotometer after its reaction with thiobarbituric acid at 532 nm. MDA concentration is expressed as nM/mg protein [77].…”

Section: Malondialdehyde (Mda) Levelsmentioning

confidence: 99%

Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder

et al. 2022

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“…There is also a role for Ox2R signaling in the expression of stress behaviors. Mice lacking Ox2R exhibit a blunted stress response (Yun et al, 2017) and administration of selective Ox2R antagonists blocks behavioral, cardiovascular and HPA axis responsivity to restraint stress (Grafe et al, 2017b), quinporole (Abounoori et al, 2020), cage exchange stress (Yun et al, 2017) and novelty (Beig et al, 2015) (although note that there is some evidence that signaling at Ox2R can be protective against the expression of anxiety; see (Arendt et al, 2014;Arendt et al, 2013;Staton et al, 2018;Summers et al, 2020)). Similarly, there is emerging evidence that dual orexin receptor antagonists (DORAs) may be effective anxiolytics.…”

Section: The Orexin System In Stress and Anxietymentioning

confidence: 99%

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse

et al. 2021

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An estimated 50-90% of individuals with cocaine use disorder (CUD) also report using alcohol. Cocaine users report co-abusing alcohol to 'self-medicate' against the negative emotional side effects of the cocaine 'crash', including the onset of anxiety. Thus, pharmaceutical strategies to treat CUD would ideally reduce the motivational properties of cocaine, alcohol, and their combination, as well as reduce the onset of anxiety during drug withdrawal. The hypothalamic orexin (hypocretin) neuropeptide system offers a promising target, as orexin neurons are critically involved in activating behavioral and physiological states to respond to both positive and negative motivators. Here, we seek to describe studies demonstrating efficacy of orexin receptor antagonists in reducing cocaine, alcohol-and stress-related behaviors, but note that these studies have largely focused on each of these phenomena in isolation. For orexin-based compounds to be viable in the clinical setting, we argue that it is imperative that their efficacy be tested in animal models that account for polysubstance use patterns. To begin to examine this, we present new data showing that rats' preferred level of cocaine intake is significantly increased following chronic homecage access to alcohol. We also report that cocaine intake and motivation are reduced by a selective orexin-1 receptor antagonist when rats have a history of cocaine + alcohol, but not a limited history of cocaine alone. In light of these proof-of-principle data, we outline what we believe to be the key priorities going forward with respect to further examining the orexin system in models of polysubstance use.

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“…There are data suggesting that orexin A modulates emotional/cognitive processes (e.g., motivation to obtain food) and it was reported that expectation for food reward (both palatable (chocolate) and general (chow)) activated lateral hypothalamic neurons containing orexin and other brain regions involved in feeding control [34] (Table 2). Finally, it is known that orexin A is involved in compulsive behaviors indicating that the orexin 1 receptor is implicated in obsessive-compulsive disorders [73] (Table 2).…”

Section: Findings Referencesmentioning

confidence: 99%

Involvement of the Orexinergic System in Feeding

Marcos

Coveñas

2021

Applied Sciences

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To know the processes involved in feeding, the dysregulation of hypothalamic neuropeptides promoting anorexigenic/orexigenic mechanisms must be investigated. Many neuropeptides are involved in this behavior and in overweight/obesity. Current pharmacological strategies for the treatment of obesity are unfortunately not very effective and, hence, new therapeutic strategies must be investigated and developed. Due to the crucial role played by orexins in feeding behavior, the aim of this review is to update the involvement of the orexinergic system in this behavior. The studies performed in experimental animal models and humans and the relationships between the orexinergic system and other substances are mentioned and discussed. Promising research lines on the orexinergic system are highlighted (signaling pathways, heterogeneity of the hypothalamic orexinergic neurons, receptor-receptor interaction, and sex differences). Each of the orexin 1 and 2 receptors plays a unique role in energy metabolism, exerting a differential function in obesity. Additional preclinical/clinical studies must be carried out to demonstrate the beneficial effects mediated by orexin receptor antagonists. Because therapies applied are in general ineffective when they are directed against a single target, the best option for successful anti-obesity treatments is the development of combination therapies as well as the development of new and more specific orexin receptor antagonists.

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The Effect of Orexin Receptor Antagonism on Quinpirole-Induced Compulsive-Like Checking Behavior in Rats

Cited by 15 publications

References 29 publications

Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder

Smo-Shh Agonist Purmorphamine Prevents Neurobehavioral and Neurochemical Defects in 8-OH-DPAT-Induced Experimental Model of Obsessive-Compulsive Disorder

The orexin (hypocretin) neuropeptide system is a target for novel therapeutics to treat cocaine use disorder with alcohol coabuse

Involvement of the Orexinergic System in Feeding

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