Aa. Genazzani et al., CHARACTERIZATION OF METABOTROPIC GLUTAMATE RECEPTORS NEGATIVELY LINKED TO ADENYLYL-CYCLASE IN BRAIN-SLICES, Brain research, 622(1-2), 1993, pp. 132-138
We have characterized the pharmacological profile of activation of met
abotropic glutamate receptors negatively linked to adenylyl cyclase (m
GluR(down cAMP)) in brain slices. Among the putative mGluR agonists, S
,1R',2R',3R')-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) and (1S,3R)
-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), were the most poten
t inhibitors of forskolin-stimulated cAMP formation in hippocampal sli
ces, followed by ibotenate, L-2-amino-3-phosphonopropionate (AP3), qui
squalate, L-glutamate and beta-N-methylamino-L-alanine (BMAA). Inhibit
ion of forskolin-stimulated cAMP formation by DL-2-amino-4-phosphonobu
tanoate (AP4) was biphasic, suggesting that the drug interacts with mo
re than one mGluR(down cAMP) subtype. Both L-AP4 and L-serine-O-phosph
ate (a restricted analogue of AP4) were much more effective in inhibit
ing forskolin-stimulated cAMP formation than their D-isomers, indicati
ng that interaction of these drugs with the mGluR(down cAMP) is stereo
selective. Despite the fact that DCG-IV and ibotenate behave as NMDA r
eceptor agonists, their effect was insensitive to MK-801. The regional
pattern of expression of mGluR(down cAMP)s, as estimated by using 1S,
3R-ACPD as an agonist, did not correlate with the steady-state levels
of mGluR2 mRNA. Thus, 1s,3R-ACPD inhibited forskolin-stimulated cAMP i
n slices from hippocampus, cerebral cortex, corpus striatum, olfactory
tubercle or hypothalamus, but not in slices from olfactory bulb or ce
rebellum; in contrast, mGluR2 mRNA levels were high in the olfactory b
ulb and very low in the corpus striatum. 1S,3R-ACPD also inhibited for
skolin-stimulated cAMP formation in cortical membranes, excluding the
involvement of trans-synaptic mechanisms in the activity of mGluR(down
cAMP)s. Finally, 1S,3R-ACPD not only failed to reduce, but rather enh
anced, norepinephrine or N-ethylcarboxamidoadenosine (NECA)-stimulated
cAMP formation in hippocampal slices, indicating the existence of mul
tiple levels of interaction between mGluRs and adenylyl cyclase activi
ty.