The Journal of Neuroscience, October 15, 2000, 20(20):7782-7789
A Common Signaling Pathway for Striatal NMDA and Adenosine
A2a Receptors: Implications for the Treatment of
Parkinson's Disease
Joanne E.
Nash1 and
Jonathan M.
Brotchie1, 2
1 Manchester Movement Disorder Laboratory, Division of
Neuroscience, School of Biological Sciences, University of Manchester,
M13 9PT, United Kingdom, and 2 Motac Neuroscience Ltd.,
Incubator Building, Manchester, M13 9XX, United Kingdom
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 µM) and the adenosine A2a receptor agonist CPCA (3 µM)
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 A2
receptor antagonist DMPX (100 µM), suggesting that
striatal NMDA receptors increase cAMP indirectly via stimulation of
adenosine A2a receptors. Thus, NMDA receptors and adenosine A2a 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 A2a receptor-cAMP signaling cascade
might be an important mechanism responsible for mediating parkinsonian symptoms.
Key words:
striatum; NMDA receptors; adenosine A2a
receptors; cAMP; 6-OHDA; Parkinson's disease
Copyright © 2000 Society for Neuroscience 0270-6474/00/20207782-08$05.00/0
Previous Article | Next Article
