NMDA AND KAINATE-EVOKED RELEASE OF NITRIC-OXIDE AND CLASSICAL TRANSMITTERS IN THE RAT STRIATUM - IN-VIVO EVIDENCE THAT NITRIC-OXIDE MAY PLAY A NEUROPROTECTIVE ROLE
Km. Kendrick et al., NMDA AND KAINATE-EVOKED RELEASE OF NITRIC-OXIDE AND CLASSICAL TRANSMITTERS IN THE RAT STRIATUM - IN-VIVO EVIDENCE THAT NITRIC-OXIDE MAY PLAY A NEUROPROTECTIVE ROLE, European journal of neuroscience, 8(12), 1996, pp. 2619-2634
The effects of N-methyl-D-aspartate (NMDA), kainate, S-alpha-amino-3-h
ydroxy-5-methyl-4-isoxazole propionate (AMPA) and KCl on striatal nitr
ic oxide (NO), acetylcholine (ACh), dopamine (DA), serotonin (5-HT), a
spartate (ASP), glutamate (GLU) and gamma-aminobutyric acid (GABA) rel
ease were measured in anaesthetized rats in vivo by microdialysis and
in vitro in organotypic slice cultures. Local NMDA (1-100 mu M) infusi
on by retrodialysis dose-dependently increased levels of classical tra
nsmitters, NO2-, NO3-, citrulline and arginine at similar thresholds (
10 mu M) Similar patterns of NMDA-evoked (50 mu M) release were seen i
n striatal cultures. NMDA-evoked changes were all calcium-dependent an
d blocked by NMDA (APV or MK-801) but not AMPA/kainate (DNQX) receptor
antagonists, excepting DA which could be prevented by both. In vivo,
kainate increased NO2-, NO3-, CIT and ARG levels at 50 and 100 mu M bu
t was less potent than NMDA. Kainate also evoked significant ACh, DA a
nd GLU release dose-dependently starting at 1-10 mu M whereas 5-HT, AS
P and GABA required 50 or 100 mu M doses. Kainate effects were inhibit
ed by DNQX, but not by APV, and were calcium-dependent. AMPA failed to
alter NO2-, NO3-, CIT or ARG levels at 50 or 100 mu M doses but dose-
dependently increased ACh and DA. Similar results were seen with kaina
te (50 mu M) and AMPA (50 mu M) in vitro. KCI evoked NO2-, NO3-, CIT a
nd ARG release as well as that of the classical transmitters in vivo a
nd in vitro. In vivo administration of the NO synthase inhibitor L-nit
roarginine (L-NARG; 100 mu M) significantly reduced NO2-, NO3- and CIT
levels and prevented NMDA, kainate or KCI-evoked increases. It also p
otentiated ACh, ASP, GLU and GABA release and reduced that of DA in re
sponse to 50 mu M NMDA whereas treatment with an NO-donor (SNAP; 10 mu
M) significantly reduced evoked ACh, ASP and GLU release. The NO synt
hase inhibitor L-NARG potentiated kainate-evoked ACh release and reduc
ed that of DA, although less potently than NMDA, but it had no effect
on KCI-evoked transmitter release. Overall, these results show that bo
th NMDA and kainate increase striatal NO release at similar dose-thres
holds as for classical transmitter release suggesting that NO is dynam
ically released under physiological and not just pathological conditio
ns. Reduction of striatal NO levels also potentiates calcium-dependent
transmitter release in response to NMDA and, to a lesser extent, kain
ate, whereas increasing them reduces it. This is consistent with a rol
e for NO as a neuroprotective agent in this region acting to desensiti
ze NMDA receptors.