JNJ-16259685

The differential reinforcement of low-rate (DRL) schedule is a validated operant conditioning paradigm used to assess timing-related behavior by requiring subjects to inhibit premature responses over fixed intervals. This task is increasingly used to examine impulsive action, particularly within neuropharmacological models of behavioral inhibition. While glutamatergic mechanisms are known to modulate impulsivity, the specific involvement of metabotropic glutamate (mGlu) receptors in DRL performance remains unclear. This study evaluated the effects of Group I mGlu receptor antagonists, JNJ16259685 (0, 0.1, 0.3, and 1 mg/kg) and MTEP (0, 1, 3, and 10 mg/kg), on a DRL 10-s task in male Wistar rats. Rats were trained to acquire stable performance of DRL behavior before pharmacological testing. Both drugs produced a dose-related decrease in total responses; however, statistically significant reductions were observed only with MTEP. Moreover, MTEP, but not JNJ16259685, significantly reduced non-reinforced responses, burst responses, and peak rate. JNJ16259685, but not MTEP, significantly increased reinforced responses. Neither drug affected peak time. These findings indicate a modest enhancement of response inhibition under Group I mGlu receptor blockade, with MTEP showing greater effectiveness than JNJ16259685. Biochemical assays using qPCR further revealed that JNJ16259685 and MTEP induced distinct, region-specific alterations in mGlu1 and mGlu5 receptor mRNA expression in most of the targeted regions, including the dorsal striatum, nucleus accumbens, hippocampus, and amygdala. Together, these results suggest that Group I mGlu receptor antagonism modulates impulsive action in a timing-based operant task and may involve differential regulation of mGlu1 and mGlu5 receptor mRNA expression in cortico-limbic-striatal systems.