Abstract
Typical antipsychotics, potent D2 dopamine receptor antagonists, are the most commonly used drugs in the treatment of bipolar disorders. In the central nervous system, the discovery of antagonistic interactions between A2A adenosine receptors and D2 dopamine receptors suggests that the adenosine system may be involved in the pathogenesis of different psychiatric disorders and in the therapeutic effectiveness of antipsychotic drugs. Previously, we have demonstrated an increase in A2A receptor expression and agonist affinity in platelets from psychotic patients treated with haloperidol. This result suggests that there is also a structural and functional interaction between A2A and D2 receptors in peripheral cells. In this work, we investigated the effect of different doses of typical drugs on A2A adenosine receptor binding and correlated these parameters with the severity of symptoms. We demonstrated, for the first time, that there was a strong correlation between A2A receptor affinity constant values (Kd) and drug doses in psychotic patients with a moderate severity of illness and moderate psychotic symptoms. The correlation was completely lost in patients with severe illness and severe psychotic symptoms. These results demonstrated that in platelets of patients affected by psychosis, typical antipsychotics modulated A2A receptor binding parameters; this regulation is dependent on the degree of D2 receptor occupancy in relation to the severity of psychotic symptoms, suggesting A2A receptors are a peripheral marker for individual therapy effectiveness.
Highlights
Bipolar disorder (BD) is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or more depressive episodes
We demonstrated that typical antipsychotic drugs, acting as D2 dopamine receptors (D2 DRs) antagonists, selectively affected the A2A AR affinity constant value in human platelets of BD patients under chronic treatment with these drugs
The main finding of these data is that administered typical drugs induced a reduction in A2A AR Kd values in a dose-dependent-manner, demonstrating the existence of a correlation between D2 DR occupancy and A2A AR regulation induced by the dopamine system
Summary
Bipolar disorder (BD) is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or more depressive episodes. The role of adenosine in the control of mood in BD stems from different lines of evidences: 1) during kindling phenomena adenosine is released and in several animal models it has been demonstrated that the use of adenosine agonists may have anti-kindling properties [2]; 2) caffeine, that is a non-selective antagonist for both A1 and A2A adenosine receptor (AR) subtypes, has a mania-like stimulant effects worsening the course of seasonal BD, causing a persistent state of arousal and an exacerbation of maniac symptoms [3,4,5,6]; 3) in BD an increase in purinergic turnover has been described [7] and the use of xantine-oxidase inhibitors as anti-maniac agents have been suggested [8,9].
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