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Metabotropic glutamate receptors (mGluRs) are coupled to second messenger pathways via G proteins and modulate synaptic transmission. Of the eight different types of mGluRs (mGluR1-mGluR8), mGluR4, mGluR6, mGluR7, and mGluR8 are members of group III. Group III receptors are generally located presynaptically, where they regulate neurotransmitter release. Because of their role in modulating neurotransmission, mGluRs are attractive targets for therapies aimed at treating anxiety disorders. Previously we showed that the mGluR4-selective allosteric agonist VU 0155041 reduces anxiety-like behavior in wild-type male mice. Here, we explore the role of mGluR4 in adult (6-month old) and middle-aged (12-month old) male and female mice lacking this receptor. Compared to age- and sex-matched wild-type mice, middle-aged mGluR4(-/-) male mice showed increased measures of anxiety in the open field and elevated zero maze and impaired sensorimotor function on the rotarod. These changes were not seen in adult 6-month-old male mice. In contrast to the male mice, mGluR4(-/-) female mice showed reduced measures of anxiety in the open field and elevated zero maze and enhanced rotarod performance. During the hidden platform training sessions of the water maze, mGluR4(-/-) mice swam farther away from the platform than wild-type mice at 6, but not at 12, months of age. mGluR4(-/-) mice also showed enhanced amygdala-dependent cued fear conditioning. No genotype differences were seen in hippocampus-dependent contextual fear conditioning. These data indicate that effects of mGluR4 on sensorimotor function and measures of anxiety, but not cued fear conditioning, are critically modulated by sex and age., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Metabotropic glutamate receptors (mGluRs) modulate glutamatergic and GABAergic neurotransmission. mGluR8, a member of group III receptors, is generally located presynaptically where it regulates neurotransmitter release. Previously we reported higher measures of anxiety in 6- and 12-month-old mGluR8(-/-) male mice than age- and sex-matched wild-type mice and that acute pharmacological stimulation with the mGluR8 agonist (S)-3,4,-dicarboxyphenylglycine (DCPG) or the Positive Allosteric Modulator (PAM) AZ12216052 reduced measures of anxiety in wild-type mice. As in humans and animals, ageing is associated with enhanced measures of anxiety following non-social and social challenges, increased understanding of these measures and how to potentially modulate them is particularly important in the elderly. Here we determined whether the effects of AZ12216052 on measures of anxiety are mediated by mGluR8 using 24-month-old mGluR8(-/-) and wild-type male mice. AZ12216052 also reduced measures of anxiety in the elevated zero maze and the acoustic startle response in mGluR8(-/-) mice. The remaining anxiolytic effects of AZ12216052 in mGluR8(-/-) mice might involve mGluR4, as the mGluR4 PAM VU 0155041 also reduced measures of anxiety in wild-type mice. In contrast, mGluR8(-/-) mice show enhanced social interaction but AZ12216052 does not affect social interaction in wild-type mice. Thus, while mGluR8 is an attractive target to modulate measures of anxiety and social interaction, the effects of AZ12216052 on measures of anxiety likely also involve receptors other than mGluR8., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Metabotropic glutamate receptors (mGluRs), which are coupled to second messenger pathways via G proteins, modulate glutamatergic and GABAergic neurotransmission. Because of their role in modulating neurotransmission, mGluRs are attractive therapeutic targets for anxiety disorders. Previously we showed that mGluR8(-/-) male mice showed higher measures of anxiety in the open field and elevated plus maze than age-matched wild-type mice. In this study, we assessed the potential effects of acute pharmacological modulation of mGluR8 on measures of avoidable and unavoidable anxiety. In addition to wild-type mice, we also tested apolipoprotein E-deficient (Apoe(-/-)) mice, as these mice show increased levels of anxiety-like behaviors and therefore might show an altered sensitivity to mGluR8 stimulation. mGluR8 stimulation with the specific agonist DCPG, or modulation with AZ12216052, a new, positive allosteric modulator of mGluR8 reduced measures of anxiety in both wild-type mice. The effects of mGluR8 positive allosteric modulators, which only affect neurotransmission in the presence of extracellular glutamate, seem particularly promising for patients with anxiety disorders showing benzodiazepine insensitivity., (Copyright 2010 Elsevier B.V. All rights reserved.)

Metabotropic glutamate receptors (mGluRs) modulate glutamatergic and GABAergic neurotransmission. mGluR8 is generally located presynaptically where it regulates neurotransmitter release. Previously we reported that 6-month-old mGluR8(-/-) male mice show higher measures of anxiety in anxiety tests involving avoidable anxiety-provoking stimuli than age-matched wild-type male mice. In wild-type mice, middle-aged females and males show higher measures of anxiety in such tests and reduced spatial learning than young adults. In this study we evaluated in middle-aged mice the effects of mGluR8 deficiency on measures of anxiety involving avoidable and unavoidable anxiety-provoking stimuli and on cognitive performance and whether these effects are sex-dependent. Female and male mGluR8(-/-) mice showed increased measures of anxiety in the open field. In contrast, male mGluR8(-/-) mice showed increased but female mGluR8(-/-) mice decreased measures of anxiety in the elevated plus maze and the acoustic startle response. mGluR8 deficiency impaired novel location recognition and spatial memory retention in the water maze. The impairment in spatial memory retention in the water maze, but not in novel location recognition, was more pronounced in female than male mice. Thus, potential sex differences in the therapeutic effects of mGluR8 modulation to reduce measures of anxiety and improve cognitive performance should be carefully considered.