PT  - JOURNAL ARTICLE
AU  - Gerard J Marek
AU  - Allyson A Salek
TI  - Extending the specificity of differential-reinforcement-of-low rate 72-s (DRL 72-s) behavior for screening antidepressant-like effects of glutamatergic clinically validated anxiolytic or antidepressant drugs in rats
AID  - 10.1124/jpet.119.264069
DP  - 2020 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.264069
4099  - http://jpet.aspetjournals.org/content/early/2020/04/07/jpet.119.264069.short
4100  - http://jpet.aspetjournals.org/content/early/2020/04/07/jpet.119.264069.full
AB  - Both an agonist and its associated prodrug for metabotropic glutamate2/3 (mGlu2/3) receptors demonstrated anxiolytic efficacy in large, randomized, multicenter, double-blind, placebo-controlled trials studying patients with generalized anxiety disorder (GAD). These mGlu2/3 receptor agonists produced robust preclinial 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 inter-response 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 co-administered 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 snxiolytic vs antidepressant drugs; and extend testing of compounds with glutamatergic mechanisms of action.SIGNIFICANCE STATEMENT The mGlu2/3 receptor agonist and clinically validated anxiolytic drug LY354740 did not test similar to antidepressant drugs (increased reinforcers, decreased response rate, and cohesive rightward shifts in the IRT distribution) when tested on DRL 72-s behavior and also did not enhance the antidepressant-like effects of the serotonin reuptake inhibitor fluoxetine. The uncompetitive NMDA receptor antagonist ketamine increased the reinforcement rate, decreased the response rate and induced a rightward shift in the interresponse time distribution similar to antidepressant drugs; these results confirm the utility of DRL 72-s schedule of reinforcement when testing glutamatergic drugs.