Opposing roles of mGluR8 in measures of anxiety involving non-social and social challenges

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.