INTEGRATED EVENTS IN CENTRAL DOPAMINE TRANSMISSION AS ANALYZED AT MULTIPLE LEVELS - EVIDENCE FOR INTRAMEMBRANE ADENOSINE A(2A) DOPAMINE D-2AND ADENOSINE A(1) DOPAMINE D-1 RECEPTOR INTERACTIONS IN THE BASAL GANGLIA

An analysis at the network and membrane level has provided evidence th at antagonistic interactions between adenosine A(2A)/dopamine D-2 and adenosine A(1)/dopamine D-1 receptors in the ventral and dorsal striat um are at least in part responsible for the motor stimulant effects of adenosine receptor antagonists like caffeine and for the motor depres sant actions of adenosine receptor agonists. The results obtained in s tably cotransfected cells also underline the hypothesis that the intra membrane A(2A)/D-2 and A(1)/D-1 receptor interactions represent functi onally important mechanisms that may be the major mechanism for the de monstrated antagonistic A(2A)/D-2 and A(1)/D-1 receptor interactions f ound in vivo in behavioural studies and in studies on in vivo microdia lysis of the striopallidal and strioentopeduncular GABAergic pathways. A major mechanism for the direct intramembrane A(2A)/D-2 and A(1)/D-1 receptor interactions may involve formation of A(2A)/D-2 and A(1)/D-1 heterodimers leading to allosteric changes that will alter the affini ty as well as the G protein coupling and thus the efficacy to control the target proteins in the membranes. This is the first molecular netw ork to cellular integration in the nerve cell membrane and may be well suited for a number of integrated tasks and can be performed in a sho rt-time scale, in comparison with the very long-time scale observed wh en receptor heteroregulation involves phosphorylation or receptor resy nthesis. Multiple receptor-receptor interactions within the membranes through formation of receptor clusters may lead to the storage of info rmation within the membranes. Such molecular circuits can represent hi dden layers within the membranes that substantially increase the compu tational potential of neuronal networks. These molecular circuits are biased and may therefore represent part of the molecular mechanism for the storage of memory traces (engrams) in the membranes. (C) 1998 Els evier Science B.V. All rights reserved.