Author:

Abstract:

In the mammalian CNS, mGluR7 functions as a presynaptic autoreceptor to regulate glutamate release into the synaptic cleft. This evolutionary highly conserved receptor has been implicated in a variety of nervous system disorders such as epilepsy, anxiety and stress-related disorders. mGluR7-deficient mice display anxiolytic and antidepressive phenotypes, but also an impairment in memory related tasks, such as spatial and working memory learning. In particular, we found a deficit in extinction learning in an instrumental conditioning paradigm. Recently, AMN082 has been identified as a specific allosteric mGluR7 agonist that can be administered orally. In rodents, AMN082 increases stress hormone levels, elicits anti-depressive and anxiolytic effects, and facilitates extinction of taste aversion learning, indicating its possible therapeutic potential. In the current study, we have investigated the effects of chronic administration of AMN082 (14 days) on extinction learning in instrumental fear conditioning and in conditioned taste aversion. Furthermore, we have measured blood corticosterone levels and mGluR7 protein levels in murine brain sections and compared the effects to single AMN082 administration or mGluR7-deficient mice. We found that chronic AMN082 significantly impaired instrumental fear extinction learning and reversed the facilitating effect in extinction learning in the conditioned taste aversion paradigm. In contrast to single administration, chronic AMN082 did not increase blood corticosterone levels. The immunohistochemical analysis indicated that chronic administration of AMN082 significantly reduced mGluR7 protein levels throughout the brain. This reduced number of mGluR7 receptors could explain the differential effects of chronic AMN082 compared to single acute administration. Funding: IWT Johnson & Johnson (Z. C. V), Fund for Scientific Research Flanders (HG), and MRC (UK), Korea-UK collaborative grant, BBSRC (E. M.).