The effect of the mGlu5 receptor antagonist MPEP in rodent tests of anxiety and cognition: a comparison.
BACKGROUND
Antagonists at the metabotropic glutamate 5 (mGlu5) receptor produce robust anxiolytic effects in a number of rat tests. However, there is evidence that mGlu5 receptor antagonists may also impair working memory and spatial learning following intracerebroventricular administration.


OBJECTIVE
The aim of this study is to compare the effect of the potent and selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-piperidine (MPEP), administered systemically on rodent tests of cognition and anxiety.


METHODS
MPEP was assessed in the following rodent tests, 60 min following oral administration: Geller--Seifter conflict, conditioned emotional response (CER), Vogel conflict, delayed match to position (DMTP) and Morris water maze. Diazepam was also tested as a comparator.


RESULTS
MPEP had a significant anxiolytic effect, comparable in magnitude to diazepam, at 10--30 mg/kg in the two conflict and CER tasks. There was no effect of MPEP up to 30 mg/kg on working memory in the DMTP task, but at 100 mg/kg, there was a significant reduction in choice accuracy at the longest delay interval (24 s). MPEP (3--30 mg/kg) did not significantly impair spatial learning in the Morris water maze, although during the last probe trial, 30-mg/kg-treated rats were significantly less accurate than controls. In contrast, diazepam significantly impaired performance in both the DMTP and Morris water maze tests. Assessment of plasma and brain concentration of MPEP approximately 75 min following oral administration showed a dose linearity from 3 to 30 mg/kg and good brain penetration, i.e. a brain/plasma ratio of 3.1.


CONCLUSIONS
Oral administration of the selective mGlu5 receptor antagonist MPEP induces a robust anxiolytic-like effect in rat conflict tests comparable to that seen with diazepam, but in contrast to diazepam, MPEP does not impair working memory or spatial learning at anxiolytic doses.
Ballard
Theresa M
TM
PRBD-N, Neuroscience Research, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Woolley
Marie L
ML
Prinssen
Eric
E
Huwyler
Jörg
J
Porter
Richard
R
Spooren
Will
W
D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D001921:Brain / Q000378:metabolism; D002755:Choice Behavior / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D003220:Conflict, Psychological; D003975:Diazepam / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005239:Fear; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
D018691:Excitatory Amino Acid Antagonists; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine; D003975:Diazepam
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