The role of mGluR5 on the ketamine-induced affective processes in Wistar rats

Ketamine is a non-competitive NMDAR antagonist with fast-onset antidepressant properties. Ketamine has a complex mechanism of action, not only targeting the NMDAR, but also affecting other glutamatergic receptors. mGluR5 has been investigated in relation to the psychotic and anesthetic properties of ketamine, while its role in mediating the therapeutic effects of ketamine remains unknown. This thesis investigated the role of mGluR5 on the antidepressant, anxiolytic and fear memory-related effects of ketamine in adult male Wistar rats. Two sets of experiments were conducted. First, I utilized the PAM CDPPB to investigate how acute mGluR5 activation affects the therapeutic effects of ketamine (10 mg/kg). I subsequently tested the potential synergistic antidepressant effect of mGluR5 antagonism and ketamine by combining MTEP with a sub-effective dose of ketamine (1 mg/kg). Behavioral despair, locomotor activity, anxiety-like behavior, and fear memory were respectively assessed in the FST, OFT, EPM, and auditory fear conditioning. The activation of mGluR5 via CDPPB partially blocked the antidepressant effect of ketamine without changing locomotor activity. In contrast, the combinatorial administration of MTEP and ketamine exhibited a synergistic antidepressant effect. The MTEP + ketamine treatment, however, blocked the anxiolytic effect observed by sole administration of MTEP or the low dose ketamine. These results suggest that suppressed mGluR5 activity may be an underlying mechanism of the ketamine's rapid antidepressant effect.