Effect of an mGlu2/3 receptor antagonist on depressive behavior induced by withdrawal from chronic treatment with methamphetamine

Withdrawal from chronic treatment with a psychostimulant precipitates behavioral and physiological conditions similar to the symptoms of major depressive disorder (MDD). Accumulated studies have indicated that withdrawal from a psychostimulant in rodents elicits depressive phenotypes including despair and anhedonia. Recently, the modulation of the group II metabotropic glutamate (mGlu2/3) receptor has been proposed as a novel therapeutic approach to MDD. In the present study, we investigated the effect of an mGlu2/3 receptor antagonist, LY341495, on the depressive behavior induced by withdrawal from chronic treatment with a psychostimulant, methamphetamine (MAP) (5.0mg/kg/day×5 days). The rats were then tested for depressive behavior using the forced swimming test. Withdrawal from chronic treatment with MAP increased the immobility time during the forced swimming test, indicating increased depressive behavior. Systemically administered LY341495 counteracted the depressive behavior induced by withdrawal from chronic treatment with MAP. Moreover, we found that the microinjection of LY341495 into the nucleus accumbens (NAc) also counteracted the increase in the immobility time caused by withdrawal from chronic treatment with MAP. Taken together, the present results suggested that the blockade of the mGlu2/3 receptor may prevent the depressive symptoms induced by withdrawal from a psychostimulant and that the blockade of the mGlu2/3 receptor in the NAc may contribute to the antidepressant-like effects of the mGlu2/3 receptor antagonist in this test.