Received for publication June 16, 2005.
Revised August 24, 2005.
Accepted for publication August 24, 2005.

A selective allosteric potentiator of mGlu2 receptors has similar effects to an orthosteric mGlu2/3 agonist in mouse models predictive of antipsychotic activity

Abstract

Recent studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2/3) have potential utility as novel therapeutic agents for treatment of psychiatric disorders such as anxiety and schizophrenia. Agonists of mGlu2/3 receptors block amphetamine- and phencyclidine (PCP)-induced hyperlocomotor activity in rodents, two actions that may predict potential antipsychotic activity of these compounds. We now report that LY487379, a recently described selective allosteric potentiator of mGlu2, has behavioral effects similar to mGlu2/3 receptor agonists. LY487379 and LY379268, an orthosteric mGlu2/3 receptor agonist, induced similar dose-dependent reductions in PCP- and amphetamine-induced hyperlocomotor activity in C57BL6/J mice at doses that did not significantly alter spontaneous locomotor activity. These effects were blocked by the mGlu2/3 receptor antagonist LY341495. LY487379 had a short duration of action compared to LY379268. Furthermore, unlike the mGlu2/3 agonist, LY487379 reversed amphetamine-induced disruption of prepulse inhibition (PPI) of the acoustic startle reflex. When LY379268 was given chronically it failed to block amphetamine- and PCP-induced hyperlocomotor activity. The finding that the effects of an orthosteric mGlu2/3 receptor agonist in these models can be mimicked by a selective allosteric potentiator of mGlu2 suggests that these effects are mediated by the mGlu2 receptor subtype. Furthermore, these data raise the possibility that a selective allosteric potentiator of mGlu2 could have utility as a novel approach for the treatment of schizophrenia.

Key words: PPI, allosteric, glutamate, mGlu2, metabotropic receptors, schizophrenia