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Volume 17, Number 2,
Issue of January 15, 1997
pp. 607-614
Copyright ©1997 Society for Neuroscience
Activation of Hippocampal Adenosine A3 Receptors
Produces a Desensitization of A1 Receptor-Mediated
Responses in Rat Hippocampus
Received March 18, 1996; revised Oct. 28, 1996; accepted Nov. 1, 1996.
Thomas V. Dunwiddie1, 2,
Lihong Diao1,
Hea O. Kim3,
Ji-Long Jiang3, and
Kenneth A. Jacobson3
1 Program in Neuroscience, University of Colorado
Health Science Center, Denver, Colorado 80262, 2 Department
of Pharmacology, University of Colorado Health Science Center, Denver,
Colorado 80262 and Veterans Administration Medical Research Service,
Denver, Colorado 80220, and 3 Molecular Recognition
Section, Laboratory of Bioorganic Chemistry, National Institute of
Diabetes, Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, Maryland 20892
The adenosine A3 receptor is expressed in brain, but
the consequences of activation of this receptor on electrophysiological activity are unknown. We have characterized the actions of a selective adenosine A3 receptor agonist,
2-chloro-N6-(3-iodobenzyl)-adenosine-5 -N-methyluronamide
(Cl-IB-MECA), and a selective A3 receptor antagonist,
3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS 1191), in brain slices from rat hippocampus. In the CA1 region, activation of A3 receptors had no direct effects on
synaptically evoked excitatory responses, long-term potentiation, or
synaptic facilitation. However, activation of A3 receptors
with Cl-IB-MECA antagonized the adenosine A1
receptor-mediated inhibition of excitatory neurotransmission. The
effects of Cl-IB-MECA were blocked by pretreatment with MRS 1191, which
by itself had no effect on A1 receptor-mediated responses.
The presynaptic inhibitory effects of baclofen and carbachol, mediated
via GABAB and muscarinic receptors, respectively, were
unaffected by Cl-IB-MECA. The maximal response to adenosine was
unchanged, suggesting that the primary effect of Cl-IB-MECA was to
reduce the affinity of adenosine for the receptor rather than to
uncouple it. Similar effects could be demonstrated after brief
superfusion with high concentrations of adenosine itself. Under normal
conditions, endogenous adenosine in brain is unlikely to affect the
sensitivity of A1 receptors via this mechanism. However,
when brain concentrations of adenosine are elevated (e.g., during
hypoxia, ischemia, or seizures), activation of A3 receptors and subsequent heterologous desensitization of A1 receptors
could occur, which might limit the cerebroprotective effects of
adenosine under these conditions.
Key words:
adenosine;
A3 receptor;
A1
receptor;
protein kinase C;
hippocampus;
electrophysiology;
receptor
desensitization
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