Animal and clinical studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) could provide a novel approach for the treatment of anxiety disorders and schizophrenia. However, group II mGlu receptor agonists activate both mGlu2 and mGlu3, and the relative contributions of these two receptor subtypes to the actions of these drugs are not known. Thus, there is a critical need to determine whether activation of a specific group II mGlu receptor subtype (mGlu2 or mGlu3) could elicit the behavioral and electrophysiological effects of group II mGlu receptor agonists that are relevant to their potential therapeutic efficacy. Furthermore, development of tolerance and adverse effects of direct agonists could limit their clinical use. Thus, it will be important to develop novel approaches to increasing activity of these receptors that may have advantages relative to direct agonists. In recent months, a novel class of compounds has been discovered that act as selective allosteric potentiators of the mGlu2 receptor subtype. These compounds do not activate mGlu2 directly but act at an allosteric site to potentiate glutamate-induced activation of the receptor. These compounds represent the first clear departure from glutamate analogs as mGlu2 activators are the first compounds that are highly selective for mGlu2 relative to mGlu3 or other mGlu receptor subtypes. However, the functional effects of these compounds in systems relevant to the therapeutic efficacy of group II mGlu receptor agonists have not been determined. We propose a series of studies in which we will determine the effects of allosteric potentiators of mGlu2 on electrophysiological responses to group II mGlu receptor activation in cell populations that have been postulated to be important for the therapeutic effects of these compounds. In addition, we will systematically evaluate the behavioral effects of allosteric mGlu2 potentiators in animal models predictive of anxiolytic and antipsychotic activity. Finally, we will determine whether direct agonists and allosteric potentiators differ in their propensity to induce desensitization and behavioral tolerance after chronic administration. These studies will build on the exciting advances suggesting a potential therapeutic utility of group II mGlu receptor activators and could provide a novel approach to increasing activity of these receptors that for development of new therapeutic agents.
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