The purpose of this study was to investigate the possibility that arachidonic acid metabolites mediate D-2 dopamine (DA) receptor inhibition of striatal DA release. The phospholipase A2 inhibitor p-bromophenacyl bromide (BPB; 10 μM) increased electrically evoked overflow of endogenous DA from rat striatal slices and appeared to partially block the modulatory effects of the D-2 DA receptor agonist N-0437 on this release. However, BPB also increased spontaneous DA outflow in a dose-dependent manner. U-73122 (10 μM), another phospholipase A2 inhibitor, decreased evoked overflow of DA, did not affect the action of N-0437 but also increased spontaneous outflow of DA. In contrast, arachidonic acid (30 μM) produced no effects. In slices prelabeled with [3H]DA, exposure to BPB, U-73122 and nordihydroguaiaretic acid (a lipoxygenase inhibitor) significantly increased spontaneous outflow of tritium whereas the cyclooxygenase inhibitors aspirin and indomethacin did not. In low micromolar concentrations, BPB, U-73122 and nordihydroguaiaretic acid, but not aspirin and indomethacin, inhibited uptake of [3H]DA into striatal synaptosomes and binding of [3H]mazindol to the DA transporter. Only U-73122 affected D-2 DA receptor binding. Taken together, these results suggest that it is unlikely that arachidonic acid metabolites mediate the actions of release-modulating D-2 DA autoreceptors in the striatum. However, the results also suggest that certain inhibitors of arachidonic acid metabolism are relatively potent DA uptake blockers/releasers and that this action is unrelated to their inhibition of enzymes in the arachidonic acid cascade. Caution should be used when using BPB and nordihydroguaiaretic acid to study mechanisms involved in DA release, because these compounds may increase DA release and thereby appear to antagonize the effects of activation of presynaptic receptors.
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1991|
ASJC Scopus subject areas
- Molecular Medicine