The gluta
matergic hypofunction hypothesis of schizophrenia has led to the develop
ment of novel therapeutic strategies
modulating NMDA receptor function. One of these strategies targets the activation of the
metabotropic gluta
mate receptor 5 (
mGlu5 receptor) using positive allosteric
modulators (PAMs). Our?goal was to evaluate the potential for repeated ad
ministration of the
mGlu5 receptor PAM, CDPPB?(3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benza
mide) (30
mg/kg) to induce tolerance to the anti-psychotic like effect using the a
mpheta
mine-induced hyperloco
motion rat
model, and to produce receptor desensitization in
mGlu5 receptor-enriched brain regions. CDPPB dose dependently reduced the loco
motor response to a
mpheta
mine when ad
ministered acutely, and the sa
me effect was observed following 7-day pre-treat
ment regi
me. In addition, 7-day dosing of CDPPB did not affect
mGlu5 receptor density in the striatu
m, nor did it change
mGlu5 receptor PAM-induced phosphorylation of NMDA, GluN1 and GluN2b, receptor subunits in striatu
m co
mpared to the levels
measured acutely. In contrast, in the frontal cortex, repeated ad
ministration of CDPPB decreased
mGlu5 receptor density and resulted in?a?loss of its ability to increase GluN1 and GluN2b levels. Consistent with a reduction of cortical
mGlu5 receptor density and phosphorylation, CDPPB (30
mg/kg) significantly affected sleep architecture as deter
mined by cortical EEG at day one however by the seventh day of dosing all sleep changes were absent. Together these results suggest that the develop
ment of tolerance induced by the repeated treat
ment with the
mGlu5 receptor PAM, CDPPB,
may depend not only on the syste
m being
measured (sleep architecture vs psychosti
mulant induced hyperactivity), but also on the brain region involved with frontal cortex being a
more susceptible region to receptor desensitization and internalization than striatu
m.
This article is part of a Special Issue entitled ¡®Schizophrenia?