Differential effects of the mGluR5 positive allosteric modulator CDPPB in the cortex and striatum following repeated administration.
The glutamatergic hypofunction hypothesis of schizophrenia has led to the development of novel therapeutic strategies modulating NMDA receptor function. One of these strategies targets the activation of the metabotropic glutamate receptor 5 (mGlu5 receptor) using positive allosteric modulators (PAMs). Our goal was to evaluate the potential for repeated administration of the mGlu5 receptor PAM, CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide) (30 mg/kg) to induce tolerance to the anti-psychotic like effect using the amphetamine-induced hyperlocomotion rat model, and to produce receptor desensitization in mGlu5 receptor-enriched brain regions. CDPPB dose dependently reduced the locomotor response to amphetamine when administered acutely, and the same effect was observed following 7-day pre-treatment regime. In addition, 7-day dosing of CDPPB did not affect mGlu5 receptor density in the striatum, nor did it change mGlu5 receptor PAM-induced phosphorylation of NMDA, GluN1 and GluN2b, receptor subunits in striatum compared to the levels measured acutely. In contrast, in the frontal cortex, repeated administration 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 determined by cortical EEG at day one however by the seventh day of dosing all sleep changes were absent. Together these results suggest that the development of tolerance induced by the repeated treatment with the mGlu5 receptor PAM, CDPPB, may depend not only on the system being measured (sleep architecture vs psychostimulant induced hyperactivity), but also on the brain region involved with frontal cortex being a more susceptible region to receptor desensitization and internalization than striatum.
Department of Psychiatry, Merck & Co., Inc., West Point, PA 19486, USA. sophie_parmentier_batteur@merck.com
Sophie
S
Parmentier-Batteur
Julie A
JA
O'Brien
Scott
S
Doran
Shannon J
SJ
Nguyen
Rosemarie Beth
RB
Flick
Jason M
JM
Uslaner
Hank
H
Chen
Eleftheria N
EN
Finger
Theresa M
TM
Williams
Marlene A
MA
Jacobson
Pete H
PH
Hutson
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D008297:Male; D011595:Psychomotor Agitation / Q000503:physiopathology; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D012890:Sleep / Q000187:drug effects
C494553:3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; D001549:Benzamides; C578937:Grm5 protein, rat; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate