Lipids and neuroinflammation: a two-way pathway in alcohol and cocaine reward
- Autores: Macarena González Portilla
- Directores de la Tesis: Marta Rodríguez Arias (dir. tes.), Sandra Montagud Romero (codir. tes.), María Pascual Mora (codir. tes.)
- Lectura: En la Universitat de València ( España ) en 2023
- Idioma: inglés
- Número de páginas: 384
- Tribunal Calificador de la Tesis: Pedro Rolando Grandes Moreno (presid.), María del Carmen Blanco Gandía (secret.), Rick E Bernardi (voc.)
- Programa de doctorado: Programa de Doctorado en Investigación en Psicología por la Universitat de València (Estudi General)
- Materias:
- Enlaces
- Tesis en acceso abierto en: RODERIC
- Resumen
Neuroinflammation is an important component in the pathophysiology associated with substance use disorder (SUD). Environmental factors such as nutrition and stress are relevant risk factors for the development of SUD and, at the same time, engage the immune response of the organism. Social defeat (SD) is a model to study the effects of social stress in rodents. Defeated mice are more vulnerable to the reinforcing effects of drugs such as alcohol or cocaine and exhibit an inflammatory profile characterized by increased microglial activity, cytokine release including interleukin (IL)-6, IL-1ß, IL-10, chemokines (CX3CL1), and toll-like receptor (TLR) activation.
The aim of this Doctoral Thesis was to study the relationship between lipids and the neuroinflammatory response in reward-related behavior. To do so, we adopted a dual approach. First, we demonstrated that a high-fat diet and alcohol binge drinking during adolescence increase alcohol consumption in adulthood and potentiate the concomitant immune response. Second, we observed that administration of the lipid oleoylethanolamide (OEA) (10mg/kg) modulates the reinforcing effects of alcohol in the self-administration paradigm and cocaine in the place preference conditioning (CPP). These effects resulted in gene expression changes of dopaminergic, cannabinoid and opioid receptors in the striatum and hippocampus. Furthermore, in a series of studies we evaluated the effects of OEA on the stress-induced enhancement of the reinforcing effects of alcohol and cocaine. Administration prior to SD or conditioning sessions blocked the social stress-induced potentiation of cocaine (1mg/kg) CPP. In addition, pretreatment of OEA before each SD encounter blocked the increase of TLR4 gene expression in the cerebellum. In the case of alcohol, we observed that only a chronic treatment of 10 doses after stress exposure was effective in preventing the increase in alcohol consumption in defeated mice. Finally, we used SD in male mice and vicarious SD in female mice to study the effects of OEA on behavioral alterations resulting from exposure to social stress. Treatment with OEA reversed some of these alterations and reduced the expression of IL-6 and CX3CL1 in brain reward centers.
In summary, these findings highlight the multifaceted role of lipids and their influence on the neurobiological mechanisms underlying addiction. Depending on the pattern of consumption, dietary lipids may be a risk factor for alcohol and cocaine use. In turn, endogenous lipid signaling are potential therapeutic targets, given their modulatory role in the neuroinflammatory response induced by stress and drug exposure.
