Indirect Modulation of Dopamine D 2 Receptors as Potential Pharmacotherapy for Schizophrenia: I. Adenosine Agonists

Abstract

OBJECTIVE:

To review preclinical and clinical information related to pharmacologic modulation of dopamine D₂ receptors as potential novel antipsychotic therapy. Specifically, to summarize the data that suggest a modulatory action of adenosine A_2A receptors on dopamine D₂ receptors and, therefore, a possible rational role of adenosine A_2A agonists as novel antipsychotic agents.

DATA SOURCES:

Primary and review articles were identified by MEDLINE search (from 1966 to May 1998) and through secondary sources.

STUDY SELECTION AND DATA EXTRACTION:

All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review.

DATA SYNTHESIS:

For all of the older and many of the newer antipsychotic agents, there is a strong correlation between clinical antipsychotic activity and affinity for dopamine D₂ receptors. Unfortunately, dopamine D₂ receptors are believed to also be involved in the adverse effect profile of these agents. The indirect modulation of dopamine D₂ receptors, rather than direct block, might produce antipsychotic effects without the usual adverse reactions. Several lines of evidence from animal studies suggest that the use of selective A_2A agonists might represent a novel approach to the treatment of psychoses.

CONCLUSIONS:

Dopamine receptor modulation might represent a novel antipsychotic approach or adjunct therapy. The data regarding adenosine agonists (particularly selective A_2A receptor agonists) are inconclusive at the present time. Direct clinical demonstration of effectiveness is required.