Towards an Understanding of Integrative Brain Functions

Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adensine A_2A/dopamine D₂ and adenosine A₁/dopamine D₁ receptor intractions in the basal ganglia

Kjell Fuxe ^a,* Sergi Ferré ^a, Michele Zoli ^b, Luigi F. Agnati ^b
a Dept. of Neuroscience, Karolinska Institutet, 171 77 Stockholm, ^b Section of Physiology, Dept. of Biomedical Sciences, University of Medina, 4100 Modena, Italy

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Abstract
An analysis at the network and membrane level has provided evidence that antagonistic interactions between adenosine A_2A/dopamine D₂ and adenosine A₁/dopamine D₁ receptors in the ventral and dorsal striatum are at least in part responsible for the motor stimulant effects of adenosine receptor antagonists like caffeine and for the motor depressant actions of adenosine receptor agonists. The results obtained in stably cotransfected cells also underline the hypothesis that the intramembrane A₂A/D₂ and A₁/D₁ receptor interactions represent functionally important mechanisms that may be the major mechanism for the demonstrated antagonistic A_2A/D₂ and A₁/D₁ receptor interactions found in vivo in behavioural studies and in studies on in vivo microdialysis of the striopallidal and strioentopeduncular GABAergic pathways. A major mechanism for the direct intramembrane A_2A/D₂ and A₁/D₁ receptor interactions may involve formation of A_2A/D₂ and A₁/D₁ heterodimers leading to allosteric changes that will alter the affinity as wells as the G protein coupling and thus the efficacy to control the target proteins in the membranes. This is the first molecular network 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 short-time scale, in comparison with the very long-time scale observed when receptor heteroregulation involves phosphorylation or receptor resynthesis. Multiple receptor-receptor interactions within the membranes through formation of receptor clusters may lead to the storage of information within the membranes. Such molecular circuits can represent hidden layers within the membranes that substantially increase the computational 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.

*Corresponding author: Kjell.Fuxe@neuro.ki.si

Brain Research Reviews 26 (1998) 258-273
Copyright © 1998 Elsevier Science B. V. All rights reserved.