Interaction between A1 adenosine and class II metabotropic glutamate receptors in the regulation of purine and glutamate release from rat hippocampal slices.
Electrical stimulation of rat hippocampal slices evoked the release of excitatory amino acids and purines, as reflected by a time-dependent increase in the extracellular levels of glutamate and adenosine, as well as by the increased efflux of radioactivity in slices preloaded with both [14C]glutamate and [3H]adenosine. The evoked release of excitatory amino acids and purines was amplified when slices were exposed to 8-cyclopentyl-1,3-dipropylxanthine (a selective A1 adenosine receptor antagonist), (+)-alpha-methyl-4-carboxyphenylglycine [a mixed antagonist of metabotropic glutamate receptors (mGluRs)], or (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine (a selective antagonist of class II mGluRs). In contrast, 2-chloro-N6-cyclopentyladenosine (CCPA; a selective A1 receptor agonist) or (2S,1R,2R,3R)-(2,3-dicarboxycyclopropyl)glycine (DCG-IV; a selective agonist of class II mGluRs) reduced the evoked release of excitatory amino acids and purines. CCPA and DCG-IV also reduced the increase in cyclic AMP formation induced by either forskolin or electrical stimulation in hippocampal slices. The inhibitory effect of CCPA and DCG-IV on release or cyclic AMP formation was less than additive. We conclude that the evoked release of excitatory amino acids and purines is under an inhibitory control by A1 receptors and class II mGluRs, i.e., mGluR2 or 3, which appear to operate through a common transduction pathway. In addition, although these receptors are activated by endogenous adenosine and glutamate, they can still respond to pharmacological agonists. This provides a rationale for the use of A1 or class II mGluR agonists as neuroprotective agents in experimental models of excitotoxic neuronal degeneration.
Di Iorio
P
P
Institute of Pharmacology, University of Chieti and Catania, Catania, Italy.
Battaglia
G
G
Ciccarelli
R
R
Ballerini
P
P
Giuliani
P
P
Poli
A
A
Nicoletti
F
F
Caciagli
F
F
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D018846:Excitatory Amino Acids / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000737:chemistry* / Q000166:cytology / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D009924:Organ Culture Techniques; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D014970:Xanthines / Q000494:pharmacology
D003521:Cyclopropanes; D018846:Excitatory Amino Acids; D018696:Neuroprotective Agents; D009498:Neurotoxins; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D018094:Receptors, Metabotropic Glutamate; D018047:Receptors, Purinergic P1; D014970:Xanthines; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C082313:2-(2,3-dicarboxycyclopropyl)glycine; C058394:2-chloro-N(6)cyclopentyladenosine; D018698:Glutamic Acid; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000241:Adenosine; D005998:Glycine