The mGluR5 antagonist MPEP, but not the mGluR2/3 agonist LY314582, augments PCP effects on prepulse inhibition and locomotor activity.

Phencyclidine (PCP), a non-competitive antagonist of ionotropic N-methyl-D-aspartate (NMDA) receptors, produces psychotomimetic effects, such as a disruption in prepulse inhibition (PPI) of the startle response. NMDA antagonists also induce locomotor hyperactivity in rodents. We hypothesized that, like NMDA receptors, metabotropic glutamate receptors (mGluRs) modulate PPI and locomotor activity either alone or, in the case of mGluR5, via interaction with NMDA receptors. Rats treated with the mGluR5 antagonist MPEP (2-methyl-6-phenylethynylpyridine) or the mGluR2/3 agonist LY314582, either alone or in combination with PCP, were tested in PPI and locomotor activity paradigms. Neither MPEP nor LY314582 altered PPI. MPEP, but not LY314582, potentiated the PPI-disruptive effects of PCP. MPEP alone did not alter locomotor or exploratory behavior, but augmented the complex, time-dependent locomotor-stimulating effects of PCP. LY314582 dose-dependently decreased locomotor activity and exploratory holepokes. LY314582 did not alter the PCP-induced increases in locomotor activity, but further decreased the number of holepokes. The effects of MPEP on the response to PCP may reflect the cooperation and co-localization of NMDA and mGlu5 receptors.