Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats.
In the present study, we evaluated the effects of subchronic blockade of mGluR5 by 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on learning, anxiety and levodopa-induced dyskinesia in rats. In addition, we excluded the possibility that subchronic treatment produced pharmacokinetic changes using brain microdialysis. MTEP (5 mg/kg) impaired spatial learning in a radial maze task and contextual fear conditioning (CFC) when administered acutely, and the same effect was observed following a 4-day pre-treatment regime. Similarly, MTEP (5 mg/kg) exerted anxiolytic-like effects in CFC when given before the test whether administered after acute or sub-chronic treatment. Similarly, in levodopa-induced dyskinesia, sub-chronic (7 subsequent days) treatment with MTEP (5 mg/kg) resulted in a significant reduction in abnormal involuntary movements (AIMs), comparable to single acute administration. The data indicate that tolerance does not develop to the anxiolytic and antidyskinetic effects of mGluR5 antagonist MTEP at least at the used treatment mode and tested doses. However, at least at the doses tested, also no tolerance to the memory impairing effect of MTEP was observed. Depending on the indication and model, the amnesic effects of MTEP should be taken into account as a potential limitation, also after repetitive treatment.
Gravius
Andreas
A
Department of In Vivo Pharmacology, Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, 60318, Frankfurt am Main, Germany. andreas.gravius@merz.de
Dekundy
Andrzej
A
Nagel
Jens
J
Morè
Lorenzo
L
Pietraszek
Małgorzata
M
Danysz
Wojciech
W
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007980:Levodopa / Q000009:adverse effects / Q000037:antagonists & inhibitors; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D018698:Glutamic Acid; D007980:Levodopa