G protein-coupled receptor (gpcr) heteroreceptor complexes: Insights into cocaine addiction, brain function, and neuropsychiatric disorders

• Autores: Alexander López Salas
• Directores de la Tesis: Dasiel Óscar Borroto Escuela (dir. tes.), Manuel Narváez Peláez (codir. tes.)
• Lectura: En la Universidad de Málaga ( España ) en 2023
• Idioma: español
• Tribunal Calificador de la Tesis: Luis Enrique Arroyo García (presid.), Raquel Sánchez Varo (secret.), Luca Pinton (voc.)
• Programa de doctorado: Programa de Doctorado en Biomedicina, Investigación Traslacional, y Nuevas Tecnologías en Salud por la Universidad de Málaga
• Calificación: Sobresaliente
• Materias:
  • Química
    • Bioquímica
      • Biología molecular
  • Ciencias médicas
    • Psiquiatría
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• Resumen

  • The thesis explores the intricate world of G-protein-coupled receptor (GPCR) homo- and heteroreceptor complexes, with a focus on their existence within the Central Nervous System (CNS). Allosteric receptor-receptor interactions in these complexes represent a novel frontier in molecular neuroscience, influencing signal integration across diverse tissues. The research aims to shed light on these complexities and their role in mental and neurological disorders. The primary objective is to understand GPCR heteroreceptor complexes and their allosteric interactions, particularly in neuronal and astroglial cells. This exploration is driven by the potential implications for mental and neurological disorders. Three specific aims are delineated: 1) Investigate the impact of combined treatment with OSU-6162 and CGS 21680 on cocaine self-administration and A2AR-D2R heteroreceptor complexes. 2) Examine changes in FGFR1 homoreceptor complexes in a genetic rat model of major depression. And 3) Characterize the 5-HT2C-OXTR heteroreceptor complexes in depression models, assessing the influence of ketamine. Modern techniques, including super-resolution imaging, spatial intensity distribution analysis, and in situ Proximity Ligation Assays (PLA), are employed to investigate the stoichiometry of receptor protomers in GPCR heteroreceptor complexes. The thesis uses these methods to explore changes in receptor complexes and their interactions in response to various treatments and conditions. In Chapter 1 experimental data showed that combined treatment with OSU-6162 and CGS 21680 induces significant changes in A2AR-D2R heteroreceptor complexes without altering cocaine self-administration. The potential role of astrocytes in modulating these effects is explored, suggesting a link between altered ATP and adenosine release and cocaine self-administration outcomes. In Chapter 2, the study introduces in situ PLA as a valuable method for studying FGFR1 homoreceptor complexes. Disturbances in the activation of FGFR1 homoreceptor complexes are identified in the hippocampal system of a genetic rat model of depression, offering new insights into major depression. In in a final Chapter 3, the research reveals a decrease in 5-HT2C-OXTR heterodimer expression in the hippocampus of depressed rats, providing a potential link to the development of the depressive phenotype. The impact of ketamine on this complex is explored, indicating a non-significant increase in expression. The thesis concludes by emphasizing the collective contribution of the three chapters in advancing our understanding of adenosine, dopamine, and serotonin receptor complexes. These insights provide a foundation for potential therapeutic interventions in neurological disorders. Additionally, the thesis discusses two recent publications, highlighting the role of oxytocin receptors in GPCR heteroreceptor networks and the susceptibility of GPCR heteroreceptor complexes to neurotoxins, offering valuable insights into the complex interactions within these networks and their implications for brain function and disorders. In summary, the research presented in this thesis significantly contributes to unraveling the molecular intricacies of GPCR heteroreceptor complexes, paving the way for a deeper understanding of neurological disorders and potential therapeutic interventions.