NMDA Receptors Modulate Dopamine Loss due to Energy Impairment in the Substantia Nigra but not Striatum.
Defects in energy metabolism have been detected in
patients with Parkinson's disease and have been
proposed as a contributing factor in the disease.
Previous in vitro studies showed that NMDA receptors
contribute to the loss of dopamine neurons caused by
the metabolic inhibitor malonate. In vivo, it is not
known whether this interaction occurs through a
postsynaptic action on the cell body in the
substantia nigra or through a presynaptic action at
the dopamine terminal in the striatum. So we could
discern the anatomical level of NMDA receptor
involvement, rats were infused with malonate, either
into the left striatum or into the left substantia
nigra. NMDA receptors were locally blocked by an
intranigral or intrastriatal coinfusion of malonate
plus MK-801 followed by a second infusion of MK-801 3
h later. Animals were examined at 1 week for striatal
and nigral dopamine and GABA levels. Intranigral
infusion of malonate (0.5 mumol) produced an
approximate 50% loss of both nigral dopamine and
GABA. MK-801 (0.1 mumol) provided significant
protection against both nigral dopamine and GABA loss
and against anterograde damage to dopamine terminals
in the striatum. Intrastriatal administration of
malonate (2 mumol) produced a 68 and 35% loss of
striatal dopamine and GABA, respectively. In contrast
to intranigral administration, intrastriatal blockade
of NMDA receptors did not protect against striatal
dopamine loss, although GABA loss was significantly
attenuated. Core body temperature monitored several
hours throughout the experiment was unchanged.
Consistent with a lack of effect of NMDA antagonists
on malonate-induced toxicity to dopamine neurons in
striatum, intrastriatal infusion of NMDA had a
pronounced effect on long-term GABA toxicity with
little effect of dopamine loss. These findings are
consistent with a postsynaptic action of NMDA
receptors on mediating toxicity to dopamine neurons
during impaired energy metabolism. Copyright 2000
Academic Press.
Exp Neurol 2000 Feb;161(2):638-646
Zeevalk GD, Manzino L, Sonsalla PK
University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, 08854, USA.
PMID: 10686083
<http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10686083&dopt=Abstract>
janet paterson
52 now / 41 dx / 37 onset
a new voice: http://www.geocities.com/janet313/
613 256 8340 PO Box 171 Almonte Ontario Canada K0A 1A0
