The effect of mGlu₈ deficiency in animal models of psychiatric diseases

Abstract

The metabotropic glutamate receptor subtype 8 (mGlu 8 ) is presynaptically located and regulates the release of the transmitter. Dysfunctions of this mechanism are involved in the pathophysiology of different psychiatric disorders. mGlu 8 deficient mice have been previously investigated in a range of studies, but the results are contradictory and there are still many open questions. Therefore, we tested mGlu 8 -deficient animals in different behavioral tasks that are commonly used in neuropsychiatric research. Our results show a robust contextual fear deficit in mGlu 8 -deficient mice. Furthermore, novel object recognition, chlordiazepoxide-facilitated extinction of operant conditioning and the acoustic startle response were attenuated by mGlu 8 deficiency. We found no changes in sensory processing, locomotor activity, prepulse inhibition, phencyclidine-induced changes in locomotion or prepulse inhibition, operant conditioning, conditioned fear to a discrete cue or in animal models of innate fear and post-traumatic stress disorder. We conclude that mGlu 8 might be a potential target for disorders with pathophysiological changes in brain areas where mGlu 8 modulates glutamate and gamma-amino butyric acid (GABA) transmission. Our data especially point to anxiety disorders involving exaggerated contextual fear, such as generalized anxiety disorders, and to conditions with disturbed declarative memory.

The effects of mGlu7 receptor modulation in behavioural models sensitive to antidepressant action in two mouse strains

“…Despite this caveat, there is still much evidence to suggest that AMN082 elicits its effect through a glutamatergic mechanism as the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione attenuated the antidepressant-like effects of AMN082 (Bradley et al, 2011), MMPIP attenuated the antidepressant-like effect of AMN082 in rats (PaluchaPoniewiera and Pilc, 2012), and the influence of AMN082 on freezing behaviour has been shown to be mediated through nonmonoaminergic mechanisms (Toth et al, 2012). Furthermore, data collected through both pharmacological modulation and genetic ablation of the mGlu 7 receptor are in agreement with this proposition (Siegl et al, 2008;Fendt et al, 2010;Bahi et al, 2012). There is also evidence indicating that MMPIP can block the behavioural effects of AMN082 (Li et al, 2010;Bahi et al, 2012).…”

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

“…Consistent with a role for mGluR8 in the regulation of anxiety, increased measures of anxiety in the open field and the elevated plus maze, and an increased acoustic startle response were seen in 6- and 12-month-old mGluR8 −/− male mice [7–9]. These effects seem age-dependent as no genotype differences were seen in the elevated plus maze or elevated zero maze in 3-month-old mice [10]. While potential effects of mGluR8 deficiency in utero , during postnatal development, or during early adulthood might have contributed to the observed behavioral phenotype, they do not seem required for the anxiety modulating effects.…”

Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder

“…While there have been mixed reports about the effect of mGluR agonists on fear conditioning, in general, mGluR antagonists and genetic deletion of mGluRs in the limbic regions of the brain appear to impair both consolidation and extinction of fear conditioning 125–130 . Activation of mGluR1-containing receptors in the BLA is known to enhance fear learning 131 .…”