Involvement of pre-proenkephalin and sigma-1 receptors in nicotine addiction
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Document Type
Document Version
Author
Director
Maldonado, Rafael
Martín García, Elena
Montero Pastor, Ana
Martín García, Elena
Montero Pastor, Ana
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Publication Date
Pages
325 p.
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Citation
Kummer, S. Involvement of pre-proenkephalin and sigma-1 receptors in nicotine addiction. Universitat Pompeu Fabra; 2020. handle: http://hdl.handle.net/10803/669683
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Citation
Doctoral program
Programa de doctorat en Biomedicina
Abstract
El tabaquismo es la principal causa de muerte evitable en todo el mundo, responsable de más de 7 millones de muertes al año. La nicotina es el principal componente psicoactivo del tabaco y la responsable de sus propiedades adictivas. Aunque dejar de fumar produce importantes beneficios para la salud, alrededor del 80% de los ex fumadores recaen en el primer mes. La nicotina actúa sobre los receptores de acetilcolina nicotínicos, sin embargo, la adicción a la nicotina es una enfermedad cerebral compleja que implica la participación de varios sistemas de neurotransmisores. En un primer enfoque, combinamos sofisticados modelos de comportamiento operante con herramientas genéticas y quimiogenéticas mediadas por virus para demostrar que la señalización de opioides y la señalización glutamatérgica corticostriatal contribuyen de manera crítica a las propiedades de refuerzo de la nicotina. Además, revelamos que la autoadministración de nicotina desencadena la plasticidad estructural en la zona central y la corteza del núcleo accumbens (NAc). Curiosamente, la plasticidad estructural fue impulsada exclusivamente por la autoadministración contingente de nicotina, pero no por la administración no contingente, concluyendo que el comportamiento dirigido a objetivos y el condicionamiento son necesarios para activar los mecanismos que subyacen a la plasticidad estructural. En un segundo enfoque, demostramos por primera vez la implicación del receptor sigma-1 (Sig-1R), un nuevo tipo de receptor que se cree que carece de su propia maquinaria de señalización específica, en la recaída la búsqueda de nicotina. El bloqueo agudo de Sig-1Rs disminuyó significativamente el restablecimiento de la búsqueda de nicotina inducida por estimulos asociados al inhibir las adaptaciones neurobiológicas en la corteza prefrontal medial y el NAc, incluidos los receptores Sig-1R, glutamatérgicos, colinérgicos y opioides. En conjunto, nuestro estudio proporciona nuevos conocimientos sobre la participación de la señalización opioide, glutamatérgica y Sig-1R en la adicción a la nicotina que pueden ayudar a desarrollar nuevas estrategias terapéuticas para tratar la adicción a la nicotina.
Tobacco smoking is the leading cause of preventable death worldwide, responsible for more than 7 million deaths per year. Nicotine is the main psychoactive component of tobacco and responsible for its addictive properties. Although smoking cessation produces significant health benefits, around 80% of former smokers relapse within the first month. Nicotine acts on nicotinic acetylcholine receptors, however, nicotine addiction is a complex brain disease that involves the participation of several neurotransmitter systems. In a first approach, we combined sophisticated operant behavioral models with genetic and virus-mediated chemogenetic tools to demonstrate that opioid signaling and corticostriatal glutamatergic signaling critically contribute to the reinforcing properties of nicotine. We further revealed that nicotine self-administration triggers structural plasticity in the nucleus accumbens (NAc) core and shell. Interestingly, structural plasticity was singularly driven by contingent nicotine self-administration, but not non-contingent nicotine administration, concluding that goal-directed behavior and conditioning are necessary to trigger the mechanisms that underly structural plasticity. In a second approach, we demonstrated for the first time the implication of the sigma-1 receptor (Sig-1R), a novel receptor type that is thought to lack its own specific signaling machinery, in the relapse to nicotine-seeking. Acute blockade of Sig-1Rs significantly decreased cue-induced reinstatement of nicotine-seeking by inhibiting neurobiological adaptations in the medial prefrontal cortex and NAc, including Sig-1Rs, glutamatergic, cholinergic and opioid receptors. Together, our study provided new insights about the involvement of opioid, glutamatergic and Sig-1R signaling in nicotine addiction that can help to develop new therapeutic strategies to treat nicotine addiction.
Tobacco smoking is the leading cause of preventable death worldwide, responsible for more than 7 million deaths per year. Nicotine is the main psychoactive component of tobacco and responsible for its addictive properties. Although smoking cessation produces significant health benefits, around 80% of former smokers relapse within the first month. Nicotine acts on nicotinic acetylcholine receptors, however, nicotine addiction is a complex brain disease that involves the participation of several neurotransmitter systems. In a first approach, we combined sophisticated operant behavioral models with genetic and virus-mediated chemogenetic tools to demonstrate that opioid signaling and corticostriatal glutamatergic signaling critically contribute to the reinforcing properties of nicotine. We further revealed that nicotine self-administration triggers structural plasticity in the nucleus accumbens (NAc) core and shell. Interestingly, structural plasticity was singularly driven by contingent nicotine self-administration, but not non-contingent nicotine administration, concluding that goal-directed behavior and conditioning are necessary to trigger the mechanisms that underly structural plasticity. In a second approach, we demonstrated for the first time the implication of the sigma-1 receptor (Sig-1R), a novel receptor type that is thought to lack its own specific signaling machinery, in the relapse to nicotine-seeking. Acute blockade of Sig-1Rs significantly decreased cue-induced reinstatement of nicotine-seeking by inhibiting neurobiological adaptations in the medial prefrontal cortex and NAc, including Sig-1Rs, glutamatergic, cholinergic and opioid receptors. Together, our study provided new insights about the involvement of opioid, glutamatergic and Sig-1R signaling in nicotine addiction that can help to develop new therapeutic strategies to treat nicotine addiction.
Keywords
Nicotine addiction, Endogenous opioid system, Sigma-1 receptor, Cue-induced reinstatement, DREADD, Adicción a nicotina, Sistema opioide endógeno, Receptor sigma-1, Restablecimiento inducido por estímulos asociados
Subjects
615 - Pharmacology. Therapeutics. Toxicology. Radiology
Publisher
Universitat Pompeu Fabra
