Metabotropic glutamate receptors, transmitter output and fatty acids: Studies in rat brain slices

1 The effects of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD), a non-selective agonist of the metabotropic glutamate receptors (mGluRs), have been studied in rat cortical and striatal slices by measuring the depolarization-induced output of D-[H-3]-aspartate (D-[H-3]-Asp) and of [H-3]-glutamate ([H-3]-Glu), neosynthesized from [H-3]-glutamine. 2 In cortical slices, 1S,3R-ACPD potentiated the depolarization-induced (KCl, 30 mM) output of both D-[H-3]-Asp and [H-3]-Glu. The potentiation, obtained at 300 mu M 1S,3R-ACPD was 65+/-6% for D-[H-3]-Asp and 56+/-10% for [H-3]-Glu. Conversely, in striatal slices, 1S,3R-ACPD reduced the depolarization-induced transmitter output. The reduction, obtained at 300 mu M of the agonist, was 60+/-8% for D-[H-3]-Asp and 50+/-5% for neosynthesized [H-3]-Glu. 3 Bovine serum albumin (BsA, 15 mu M), which is able to bind locally produced fatty acids, completely eliminated the potentiating effect 1S,3R-ACPD had on D-[H-3]-Asp output from cortical slices. Low concentrations of arachidonic acid (1-10 mu M) or of oleic acid (1-10 mu) added to BSA-containing perfusion medium, restored this potentiating effect. BSA, however, had no effect on the inhibitory action of 1S,3R-ACPD in striatal slices. 4 Bromophenacyl bromide (100 mu M), an inhibitor of phospholipase A(2), and RG80267 (100 mu M), an inhibitor of diacylglycerol lipase, have been shown to inhibit fatty acid production. These compounds prevented the potentiating effect of 1S,3R-ACPD on D-[H-3]-Asp-output in cortical slices. 5 Indomethacin (100 mu M), an inhibitor of cyclo-oxygenases, plus nordihydroguaiaretic acid (100 mu M), an inhibitor of lipoxygenases, increased D-[H-3]-Asp output in cortical slices perfused with BSA-containing medium. 6 These experiments suggest that the mGluR-mediated potentiation of transmitter output requires the availability of unsaturated fatty acids, such as arachidonic or oleic acids, in cortical slices. In contrast, the mGluR-induced inhibition of transmitter output is not dependent upon fatty acid availability in striatal slices. The requirement of both unsaturated fatty acids and 1S,3R-ACPD in the facilitation of transmitter exocytosis may play an important role in the regulation of synaptic plasticity.