Study Reveals the Reason Underlying Dissimilar Outcomes With Antagonist Drugs in Brain Disorders

A new study led by researchers at the University of Barcelona in Spain recently revealed the reason behind discrepant outcomes when administering antagonist drugs for brain disorders. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS) and is entitled “Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer”.

Parkinson’s disease is a progressive neurodegenerative disorder that develops gradually, with patients usually experiencing the first symptoms around the age of 60 or older. As the disease progresses, the symptoms worsen from a barely noticeable tremor in the hands to serious difficulties in speaking, locomotion, coordination and balance. The disease is caused by the loss of the neurotransmitter dopamine due to premature death of dopaminergic neurons in the brain, which play an important role in voluntary movement and behavioral processes (mood, stress, reward, addiction). It is estimated that up to 10 million people worldwide suffer from the disease. There is currently no cure for Parkinson’s or therapies able to halt or slow disease progression.

Adenosine A2A receptors are abundantly expressed within the basal ganglia, a group of structures in the brain involved in movement coordination. Adenosine A2A receptors are members of the G protein-coupled receptor (GPCR) family. Antagonists of adenosine A2A receptors can modulate the release of key neurotransmitters in the basal ganglia, modulating motor activity. These A2A receptor antagonists have been shown to improve motor symptoms in animal models of Parkinson’s disease, being considered potential therapeutic drugs for the disease. However, it has also been reported that these antagonists can block physiological responses, including motor responses.

It is known that adenosine A2A receptors bind to dopamine D2 receptors in the basal ganglia. This interaction between the two can control movement, and abnormalities in this process can lead to severe movement disorders like Parkinson’s disease. Researchers have now characterized this interaction further and discovered that A2A receptors and D2 receptors actually form a tetrameric structure comprising a homodimer of A2A and a homodimer of D2, instead of a heteromer of A2A and D2 receptors.

The traditional view is that antagonists simply act by competing with natural agonists to bind to specific receptors blocking their activity. Now, based on their findings, researchers propose that a certain concentration of an adenosine receptor A2A antagonist, as is the case of caffeine, can block movement inhibition induced by adenosine; however, in higher concentrations, the antagonist may no longer be able to suppress the adenosine effect and ends mimicking the role of adenosine, limiting the function of dopamine D2 receptors in the brain. In the latter case, the adenosine receptor A2A antagonist will not act as an effective therapeutic drug, but instead as a drug that impairs movement control.

The team believes that this tetrameric structure formed by A2A and D2 receptors can therefore explain the inconsistencies reported when testing antagonist drugs, and suggests that this finding can most likely be extrapolated to the effect of other antagonist drugs in alternative receptors.

The authors concluded that “the binding of receptors of hormones, neurotransmitters and neuromodulators forming tetrameters may explain the contradictory results obtained in therapies based on the use of an antagonist drug of a receptor to alter the action of the other receptor and underlines that the success of this type of treatments relies on administering an appropriate dose of the drug”.

In simple terms, and using caffeine as an example of an A2A receptor antagonist, the results explain that an appropriate dose of caffeine might offer a clinical benefit in terms of movement control, whereas an excessive consumption might actually have the opposite effect leading to impairment in movement control.