A common signaling pathway for striatal NMDA and adenosine A2a receptors: implications for the treatment of Parkinson's disease.
The striatum is the major input region of the basal ganglia, playing a pivotal role in the selection, initiation, and coordination of movement both physiologically and in pathophysiological situations such as Parkinson's disease. In the present study, we characterize interactions between NMDA receptors, adenosine receptors, and cAMP signaling within the striatum. Both NMDA (100 micrometer) and the adenosine A(2a) receptor agonist CPCA (3 micrometer) increased cAMP levels (218.9 +/- 19.9% and 395.7 +/- 67.2%, respectively; cf. basal). The NMDA-induced increase in cAMP was completely blocked when slices were preincubated with either the NMDA receptor antagonist 7-chlorokynurenate or the adenosine A(2) receptor antagonist DMPX (100 micrometer), suggesting that striatal NMDA receptors increase cAMP indirectly via stimulation of adenosine A(2a) receptors. Thus, NMDA receptors and adenosine A(2a) receptors might share a common signaling pathway within the striatum. In striatal slices prepared from the 6-hydroxydopamine-lesioned rat model of Parkinson's disease, NMDA receptor-mediated increases in cAMP were greater on the lesioned side compared with the unlesioned side (349.6 +/- 40.2% compared with 200.9 +/- 21.9% of basal levels, respectively). This finding substantiates previous evidence implicating overactivity of striatal NMDA receptors in parkinsonism and suggests that a common NMDA receptor-adenosine A(2a) receptor-cAMP signaling cascade might be an important mechanism responsible for mediating parkinsonian symptoms.
Nash
J E
JE
Manchester Movement Disorder Laboratory, Division of Neuroscience, School of Biological Sciences, University of Manchester, M13 9PT, United Kingdom.
Brotchie
J M
JM
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000628:therapy; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D016194:Receptors, N-Methyl-D-Aspartate; D018047:Receptors, Purinergic P1; D015102:3,4-Dihydroxyphenylacetic Acid; D016202:N-Methylaspartate; D016627:Oxidopamine; D000242:Cyclic AMP; D004298:Dopamine