Pbs. Clarke et M. Reuben, INHIBITION BY DIZOCILPINE (MK-801) OF STRIATAL DOPAMINE RELEASE INDUCED BY MPTP AND MPP(- POSSIBLE ACTION AT THE DOPAMINE TRANSPORTER() ), British Journal of Pharmacology, 114(2), 1995, pp. 315-322
1 The NMDA-type glutamate receptor antagonist, dizocilpine (MK-801) ca
n protect against neurotoxicity associated with 1-methyl-4-phenyl-1,2,
3,6-tetrahydropyridine (MPTP) and its principal metabolite, the 1-meth
yl-4-phenylpyridinium ion (MPP(+)). It has been suggested that these n
eurotoxic effects may be mediated by release of excitatory amino acids
, but possible alternative mechanisms have;been little investigated. 2
MPTP and MPP(+) (0.1-1000 mu M) were tested in superfused rat striata
l synaptosomes preloaded with [H-3]-dopamine. Both MPTP (10 mu M and h
igher) and MPP(+) (1 mu M and higher) evoked an immediate and concentr
ation-dependent release of [H-3]-dopamine. The maximal effect exceeded
that achievable with nicotine. For subsequent experiments, submaximal
concentrations of MPTP (50 mu M) and MPP(+) (10 mu M) were tested. 3
MK-801 (0.1-100 mu M) inhibited responses to MPTP (50 mu M) and MPP(+)
(10 mu M) in a concentration-dependent manner. However, further tests
of NMDA-type glutamate receptor involvement proved negative. Response
s to MPTP or MPP(+) were unaffected by the omission of Mg2+ or Ca2+ an
d were not reduced by the NMDA receptor antagonists, AP-7 (200 mu M) a
nd kynurenic acid (300 mu M). In this assay, N-methyl-D-aspartate (eve
n in the absence of Mg2+ and with added glycine and strychnine) did no
t evoke [H-3]-dopamine release. 4 In crude membrane preparations of ra
t cerebral cortex, MPTP and MPP(+) inhibited high-affinity [H-3]-nicot
ine binding to nicotinic cholinoceptors (IC50 1.8 mu M and 26 mu M, re
spectively). 5 [H-3]-dopamine release evoked by nicotine (1 mu M) was
blocked by the nicotinic antagonists, mecamylamine and chlorisondamine
, and by MK-801 (all at 100 mu M); K+-evoked release was not affected.
Release evoked by MPTP and MPP(+) was significantly attenuated by MK-
801 but not by mecamylamine or chlorisondamine. 6 At a high concentrat
ion (10 mu M), the selective dopamine uptake inhibitor, nomifensine, c
ompletely blocked [H-3]-dopamine release evoked by amphetamine 0.3 mu
M and MPP(+) 10 mu M, attenuated responses to MPTP 50 mu M and did not
affect responses to 12 mM K+. MK-801 100 mu M evinced a similar profi
le but was less effective. 7 MK-801 inhibited [H-3]-dopamine uptake in
striatal synaptosomes with an IC50 of 115 mu M. 8 It is concluded tha
t high concentrations of MK-801 inhibit the acute dopamine release evo
ked by MPTP and MPP(+) in synaptosomes. This antagonism may occur, at
least in part, through inhibition of the cell membrane dopamine transp
orter. MPTP and MPP(+) also appear to interact with brain nicotinic ch
olinoceptors but the functional consequences of this interaction are n
ot yet clear.