PET Imaging of the Interaction between Adenosine A2A and Dopamine D2 Receptors in Animal Models of Brain Diseases

This thesis focuses on the antagonistic interactions between adenosine and dopamine in living mammals, mediated through adenosine A2A and dopamine D2 receptors. These interactions are crucial in locomotor activation, goal-directed behavior, motor control, and reward-related behavior. The reciprocal interactions primarily occur in specific neurons and astrocytes within the striatal region and nucleus accumbens. In striatal membrane preparations, adenosine negatively affects the affinity and signal transduction of D2 receptors by interacting with A2A receptors. The proximity of A2A and D2 receptors in biomembranes allows them to co-aggregate, co-internalize, and co-desensitize. They form heteromeric complexes, contributing to the allosteric receptor-receptor interactions responsible for the antagonistic effects observed between adenosine and dopamine. These interactions have implications for treating various neurological and psychiatric disorders such as Parkinson's disease, schizophrenia, substance abuse, and attention deficit hyperactivity disorder. Understanding the dynamic equilibrium between A2A-D2 receptor heteromers and homodimers in the brain is an area of ongoing research.
Positron emission tomography (PET) with suitable ligands can provide valuable in-vivo information about receptor crosstalk in living organisms. The development of novel imaging agents, including hetero-bivalent ligands, holds promise for investigating and visualizing A2A-D2 receptor interactions. Exploring the complex dynamics of these receptor interactions can pave the way for innovative therapeutic strategies and imaging techniques to better understand and treat neurological and psychiatric conditions.