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Signal Attenuation as a Rat Model of Obsessive Compulsive Disorder
Published on: January 9, 2015
Orexin 1 receptor antagonists in compulsive behavior and anxiety: possible therapeutic use
Emilio Merlo Pich1, Sergio Melotto2
1Neuroscience DTA, F. Hoffman - La Roche Basel, Switzerland.
Abstract:
Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were initially associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA) suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders. In this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1) antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioral and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.
Insights
Hypocretin/orexin system modulation is key for physiological functions. OX1 receptor antagonists show promise for treating anxiety, panic, and substance misuse disorders by targeting hypervigilance.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- The hypocretin/orexin system plays a crucial role in regulating physiological functions.
- While reduced hypocretin/orexin is linked to narcolepsy, elevated levels are associated with hypervigilance, insomnia, anxiety, and substance misuse disorders.
- Dual-activity orexin receptor antagonists (DORAs) like suvorexant are being developed for insomnia.
Purpose of the Study:
- To review the evidence supporting the development of hypocretin/orexin receptor 1 (OX1) antagonists for conditions beyond insomnia.
- To discuss the potential of OX1 antagonists in treating anxiety, panic episodes, and substance misuse disorders.
Main Methods:
- Review of existing literature on hypocretin/orexin system and its antagonists.
- Examination of studies using OX1 antagonists (SB-334867, GSK1059865, ACT-335827) in animal models.
- Analysis of data on behavioral and cardiovascular responses to stressors and panic-inducing agents.
Main Results:
- OX1 receptor antagonists have been implicated in mediating compulsive drug seeking behaviors in animal models for various substances.
- Novel selective OX1 antagonists have shown effects on behavioral and cardiovascular responses to stressors and panic-inducing agents in animals.
- Evidence suggests a role for OX1 receptors in hypervigilance states.
Conclusions:
- OX1 receptor antagonists represent a potential therapeutic avenue for anxiety, panic disorders, and substance misuse disorders.
- Further clinical data in humans is needed to fully assess the risks and benefits of OX1 receptor antagonists for these conditions.
- The development of OX1 receptor antagonists warrants consideration for Binge Eating and Anxiety Disorders.
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