Purinoceptors in the Central Nervous System

Abstract

New exciting developments on the occurrence and functional role of purinoceptors in mammalian brain were presented at the session "Purinoceptors in the central nervous system" chaired by Flaminio Cattabeni and Tom Dunwiddie at the Purines '96 international conference. The focus of the session were topics of recent interest, including the sources and mechanisms involved in ATP and adenosine release during physiological neurotransmission in hippocampus, the brain expression of the recently cloned P2 receptors, and the role of the various adenosine receptor subtypes in brain protection from neurodegeneration associated with trauma-, ischemia-and excessive excitatory amino acid neurotransmission. New important insights into the mechanisms responsible for the formation and release of adenosine into the extracellular space were provided by data obtained by Dunwiddie and coworkers in hippocampal pyramidal neurons. These data may have functional implications for the role of purines in modulation of synaptic plasticity and long-term potentiation in this brain area, and hence in cognitive functions. Buell provided an updated overview on the cloning, molecular characteristics and brain expression of various ligand-gated P2X purinoceptors; although the functional role of these receptors in mammalian brain still awaits elucidation, their widespread distribution in the nervous system strongly suggests that ATP-mediated events are more prevalent and important in brain than expected. Pedata presented data on the functional interrelationships between adenosine and glutamate in the brain, and also provided evidence for alterations of the reciprocal regulation between these two systems in aged brain, which may have important implications for both ischemia-and trauma-associated neurodegenerative events and senescence-associated cognitive impairment. Finally, von Lubitz provided novel data on the molecular mechanisms likely to be at the basis of the brain protective effects associated with the chronic stimulation of the adenosine A₃ receptor, further confirming that this receptor represents a crucial target for the development of new antiischemic and antineurodegenerative therapeutic agents.

Keywords: ATP; adenosine; aging; glutomate; metabolism; neurodegeneration; neuroprotection; receptors; release; synaptic plasticity.

Figure 1.

Summary of the inhibition of the baseline EPSC by adenosine under various conditions. Open bars represent electrodes with no added adenosine, and the effect of adenosine antagonists under these conditions would correspond to the effects of endogenous adenosine. The filled bars show data from cells recorded with electrodes filled with 5 mM adenosine, and the inhibitory effect under these conditions would be from the total of endogenous adenosine + adenosine released from the cell as a result of adenosine loading via the pipette. The hatched bar indicates cells recorded with 5 mM dideoxyadenosine (ddA) in the pipette. The antagonists used were theophylline (200 mM), 8-p-sulfophenyltheophylline (8-pSPT; 100 mM), and adenosine deaminase (ADA; 25 mg/ml). The fourth pair of bars demonstrates that including 5 mM ddA in the pipette had no significant effect on the baseline response. The last pair of bars shows that including 2 mM BaCl₂ in the superfusion buffer throughout the entire experiment had no effect on the response to adenosine or its antagonism by theophylline (compare with first set of bars). Each bar is the mean ± sem for between 4 and 11 cells; *P < 0.05, **P < 0.01 relative to no adenosine.