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Inhibition by dizocilpine (MK‐801) of striatal dopamine release induced by MPTP and MPP + : possible action at the dopamine transporter
Author(s) -
Clarke P.B.S.,
Reuben M.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb13229.x
Subject(s) - mptp , dizocilpine , chemistry , dopamine , nmda receptor , kynurenic acid , dopamine transporter , neurotoxin , phencyclidine , pharmacology , glutamate receptor , nicotine , endocrinology , medicine , dopaminergic , receptor , biochemistry , biology
1 The NMDA‐type glutamate receptor antagonist, dizocilpine (MK‐801) can protect against neurotoxicity associated with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and its principal metabolite, the 1‐methyl‐4‐phenylpyridinium ion (MPP + ). It has been suggested that these neurotoxic 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 μ m ) were tested in superfused rat striatal synaptosomes preloaded with [ 3 H]‐dopamine. Both MPTP (10 μ m and higher) and MPP + (1 μ m and higher) evoked an immediate and concentration‐dependent release of [ 3 H]‐dopamine. The maximal effect exceeded that achievable with nicotine. For subsequent experiments, submaximal concentrations of MPTP (50 μ m ) and MPP + (10 μ m ) were tested. 3 MK‐801 (0.1–100 μ m ) inhibited responses to MPTP (50 μ m ) and MPP + (10 μ m ) in a concentration‐dependent manner. However, further tests of NMDA‐type glutamate receptor involvement proved negative. Responses to MPTP or MPP + were unaffected by the omission of Mg 2+ or Ca 2+ and were not reduced by the NMDA receptor antagonists, AP‐7 (200 μ m ) and kynurenic acid (300 μ m ). In this assay, N‐methyl‐ d ‐aspartate (even in the absence of Mg 2+ and with added glycine and strychnine) did not evoke [ 3 H]‐dopamine release. 4 In crude membrane preparations of rat cerebral cortex, MPTP and MPP + inhibited high‐affinity [ 3 H]‐nicotine binding to nicotinic cholinoceptors (IC 50 1.8 μ m and 26 μ m , respectively). 5 [ 3 H]‐dopamine release evoked by nicotine (1 μ m ) was blocked by the nicotinic antagonists, mecamylamine and chlorisondamine, and by MK‐801 (all at 100 μ 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 concentration (10 μ m ), the selective dopamine uptake inhibitor, nomifensine, completely blocked [ 3 H]‐dopamine release evoked by amphetamine 0.3 μ m and MPP + 10 μ m , attenuated responses to MPTP 50 μ m and did not affect responses to 12 m m K + . MK‐801 100 μ m evinced a similar profile but was less effective. 7 MK‐801 inhibited [ 3 H]‐dopamine uptake in striatal synaptosomes with an IC 50 of 115 μ m . 8 It is concluded that high concentrations of MK‐801 inhibit the acute dopamine release evoked by MPTP and MPP + in synaptosomes. This antagonism may occur, at least in part, through inhibition of the cell membrane dopamine transporter. MPTP and MPP + also appear to interact with brain nicotinic cholinoceptors but the functional consequences of this interaction are not yet clear.