Orexin receptors as therapeutic target for addiction and anxiety disorders
Orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2) are two neuropeptides exclusively expressed by a small subpopulation of neurons located within the lateral hypothalamic area. These neuromodulators were originally thought to specifically mediate feeding and promote wakefulness. Nev...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/458450 |
| Acceso en línea: | http://hdl.handle.net/10803/458450 |
| Access Level: | acceso abierto |
| Palabra clave: | Orexins/hypocretins Cannabis Addiction Fear Anxiety Orexinas/hipocretinas Adicción Ansiedad Miedo 615 |
| Sumario: | Orexin-A and orexin-B (also known as hypocretin-1 and hypocretin-2) are two neuropeptides exclusively expressed by a small subpopulation of neurons located within the lateral hypothalamic area. These neuromodulators were originally thought to specifically mediate feeding and promote wakefulness. Nevertheless, it is now clear that they also participate in other behavioural and physiological processes, particularly those under high motivational or emotional circumstances, including reward occasions or exposure to threats. Growing evidence indicates that orexins might be involved in dysfunctional processing of these situations, highlighting their possible contribution to certain neuropsychiatric conditions such as drug addiction and anxiety disorders. By the use of behavioural and biochemical studies, the present thesis examines the role of orexin transmission in the pharmacological and reinforcing effects of cannabinoids, which represent important contributing factors for cannabis addiction. We report that orexins modulate hypothermic, antinociceptive and anxiolytic-like effects of Δ9-tetrahydrocannabinol through orexin receptor-2, whereas they contribute to the reinforcing effects of the synthetic cannabinoid WIN55,212-2 through orexin receptor-1 signalling, in part through dopamine-dependent mechanisms. On the other hand, we have investigated the influence of orexins in fear memory processing, a pivotal component of diverse anxiety disorders. We confirmed the role of both orexin receptors in the consolidation of fear memories, and we established that orexin transmission, through orexin receptor-1 stimulation, hinders the extinction of aversive memories, probably due to its influence on the communication between the amygdala and the prefrontal cortex. The findings of the present thesis reveal the therapeutic potential of orexin receptor-1 blockade as a novel target to prevent cannabis addiction, as well as to alleviate abnormal fear retention in anxiety disorders such as posttraumatic stress disorder and phobias. |
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