Several preclinical trials have evaluated the positive allosteric mGlu5 receptor modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB). In one study [34], CDPPB (10–30 mg/kg) was assessed alone and in combination with the NMDA receptor antagonist Dizocilpine (MK-801) on a task measuring cognitive set-shifting ability (the ability to switch between rules in response to feedback). Such tasks have been shown to be NMDA dependent in prior studies. Although CDPPB did not lead to any cognitive improvements on its own, it attenuated MK-801 (0.1 mg/kg)-induced impairments in a dose-dependent manner, with the 30 mg/kg dose having a greater effect than the 10 mg/kg dose across all trials. CDPPB appeared to produce its effects through a reduction in MK-801-induced perseverative responding. Another study [35] tested repeated, as opposed to acute, dosing of CDPPB, and did not find any evidence for the development of tolerance to the behavioral effects, providing proof of concept for ongoing treatment. Moreover, repeated dosing did not appear to induce tolerance to the effect on mGlu5 receptor density or phosphorylation of NMDA, NR1 (‘GluN1’) and NR2B (‘GluN2b’) receptor subunits in striatum, although tolerance
