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Altered glutamatergic synaptic transmission is among the key events defining the course of Alzheimer's disease (AD). mGlu2 receptors, a subtype of group II metabotropic glutamate receptors, regulate (as autoreceptors) fast synaptic transmission in the CNS via the controlled release of the excitatory amino acid glutamate. Since their pharmacological manipulation in rodents has been reported to affect cognition, they are potential drug targets for AD therapy. We examined the fate of these receptors in cases of AD as well as in aging PS2APP mice—a proposed model of the disease. In vitro binding of [3H]LY354740, a selective group II agonist (with selective affinity for mGlu2 receptors, under the assay conditions used) and quantitative radioautography revealed a partial, but highly significant, loss of receptors in amyloid-affected discrete brain regions of AD cases and PS2APP mice. Among the mouse brain regions affected were, above all, the subiculum but also frontolateral cortex, dentate gyrus, lacunosum moleculare and caudate putamen. In AD, significant receptor losses were registered in entorhinal cortex and lacunosum moleculare (40% and 35%, respectively). These findings have implications for the development of selective ligands for symptomatic therapy in AD and for its diagnosis.

Co-activation of group I metabotropic glutamate (mGlu) receptors and adenosine receptors resulted in an augmented cyclic AMP response in primary cultures of rat striatal neurones. L-glutamate and the selective group I agonist, (S)-dihydroxyphenylglycine (S-DHPG) evoked concentration-dependent potentiations of cyclic AMP accumulation stimulated by the adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA), with EC50 values of 3.41+/-0. 39 and 5.69+/-1.64 microM, respectively, and maximal augmentations of approximately 350% at concentrations of 100 microM. The S-DHPG potentiation was inhibited by group I mGlu receptor antagonists and a protein kinase C inhibitor, Ro 31-8220, implicating products of PI hydrolysis in this effect. Furthermore, L-glutamate and S-DHPG stimulated PI hydrolysis in striatal neuronal cultures with similar EC50 values to those observed for the augmentation of NECA cyclic AMP responses (5.19+/-1.18 and 3.78+/-1.42 microM, respectively). In situ hybridization and immunofluorescence techniques indicate that group I mGlu receptor-evoked potentiations are likely to be mediated via mGlu5 receptors, which are expressed at high levels in these cultures. In contrast to cross-chopped slices of neonatal rat striatum, of equivalent age, the group II mGlu receptor agonist, (2S, 2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) was without effect on NECA- or forskolin-stimulated cyclic AMP responses in primary striatal neuronal cultures. This lack of effect might be due to a low level of expression of group II mGlu receptors in cultured striatal neurones.