Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: I. Adenosine agonists.
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 A2A receptors on dopamine D2 receptors and, therefore, a possible rational role of adenosine A2A agonists as novel antipsychotic agents.


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


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


RESULTS
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 A2A 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 A2A receptor agonists) are inconclusive at the present time. Direct clinical demonstration of effectiveness is required.
Dixon
D A
DA
School of Pharmacy, Temple University, Philadelphia, PA 19140, USA.
Fenix
L A
LA
Kim
D M
DM
Raffa
R B
RB
D000241:Adenosine / Q000819:agonists*; D000818:Animals; D002110:Caffeine / Q000009:adverse effects; D002986:Clinical Trials as Topic; D004347:Drug Interactions; D006801:Humans; D009154:Mutation; D018377:Neurotransmitter Agents / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D018047:Receptors, Purinergic P1 / Q000145:classification; D012559:Schizophrenia / Q000188:drug therapy* / Q000209:etiology
D018377:Neurotransmitter Agents; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; D002110:Caffeine; D000241:Adenosine