Both an agonist and its associated prodrug for metabotropic glutamate2/3 (mGlu2/3) receptors demonstrated anxiolytic efficacy in large, randomized, multicenter, doubleblind, placebo-controlled trials studying patients with generalized anxiety disorder (GAD). These mGlu2/3 receptor agonists produced robust preclinical anxiolytic-like effects in rodent models. Several different mGlu2 receptor positive allosteric modulators have been found to produce antidepressant-like effects on several preclinical screening paradigms including differential-reinforcement-of-low rate 72-s (DRL 72-s) behavior (increased reinforcers, decreased response rate and cohesive rightward shifts in interresponse time (IRT) distributions). While mGlu2/3 receptor agonists have not been tested formally for therapeutic effects in treating patients with major depressive disorder (MDD), these compounds generally fail to exert antidepressant-like effects in preclinical screening paradigms and did not improve depressive symptoms in GAD trials. Thus, the present studies were designed to test the potential antidepressant-like effects of the mGlu2/3 receptor agonist 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate (LY354740) on the DRL 72-s schedule. LY354740 did not test similar to clinically validated antidepressant drugs when administered alone or when coadministered with the selective serotonin reuptake inhibitor (SSRI) fluoxetine in rats. Another glutamate-based antidepressant drug, the uncompetitive NMDA channel blocker racemic ketamine, exerted antidepressant-like effects when administered at subanesthetic doses in rats. The findings further support the specificity of rat DRL 72-s behavior when screening for anxiolytic vs antidepressant drugs; and extend testing of compounds with glutamatergic mechanisms of action.