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

Richard M. O’Connor, John F. Cryan

There is increasing evidence suggesting a role of the neurotransmitter glutamate in depression. The metabotropic glutamate (mGlu) receptors are G-protein coupled receptors, which mediate a slow modulatory response to glutamate signalling. mGlu₇ receptor is a presynaptic inhibitory autoreceptor showing great promise as a potential therapeutic target for the treatment of depression. Selective pharmacological modulators of mGlu₇ receptor have been developed; the positive allosteric modulator AMN082 and the negative modulator 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP). They remain to be extensively characterized in behavioural models sensitive to antidepressant action. Therefore, we assessed the effects of these compounds on behaviour in two different mouse strains using several preclinical tests sensitive to antidepressant pharmacological action. AMN082 (6 mg/kg) reduced immobility in the forced swim test and tail suspension test (TST) in both C57BL/6j and CD1 mice. In CD1 mice, MMPIP (10 and 30 mg/kg) significantly increased the time spent immobile in the TST, whereas this effect was restricted to a dose of 30 mg/kg in C57BL/6j mice. Administration of MMPIP with AMN082 partially attenuated the antidepressant-like effect of AMN082 in C57BL/6j mice in the forced swim test and the TST. However, this effect was absent from the CD1 strain. This further adds to the growing corpus of data promoting the targeting of mGlu₇ receptor with the aim of achieving an antidepressant effect.