In the amygdala anxiolytic action of mGlu5 receptors antagonist MPEP involves neuropeptide Y but not GABAA signaling.
Several lines of evidence indicate that inhibition of the metabotropic glutamate (mGlu) receptor 5 produces anxiolytic-like effects in rodents. Peptide neurotransmitter neuropeptide Y (NPY) produces an anxiolytic effect in rats after intraventricular or intra-amygdalar administration. Many classes of anxiolytic drugs exert their effect through the GABA-benzodiazepine (BZD) receptor complex. Therefore, in the present study we have investigated whether the anxiolytic action of MPEP (2-methyl-6-(phenylethynyl)pyridyne), an mGlu5 receptor antagonist, is mediated by a mechanism involving either the GABA-BZD receptor complex or NPY receptor. In the behavioral studies, the anxiolytic activity of MPEP (10 mg/kg, i.p.) was examined using plus-maze test. The BZD antagonist flumazenil (10 mg/kg, i.p.) was given to one group of rats and Y1 receptor antagonist BIBO 3304 (((R)-N-[[4-(aminocarbonylaminomethyl) phenyl] methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate)3304) (200 pmol/site, intra-amygdala) to the other. It was found that anxiolytic effects of MPEP were not changed by flumazenil, but were abolished by BIBO 3304. Immunohistochemical studies showed a high density of mGlu5 receptor immunoreactivity (IR) in the amygdala. The effect of MPEP on NPY expression in the amygdala was studied using immunohistochemistry (IH) and radioimmunoassay (RIA). Both methods showed a diminution of NPY IR expression, to about 43% (IH) or 81% (RIA) of the control level after multiple administrations, but we observed an increase up to 148% of the control after single MPEP administration. These effects may suggest a release of NPY from nerve terminals after MPEP administration. Our results indicate that the anxiolytic action of MPEP is conveyed through NPY neurons with the involvement of Y1 receptors in the amygdala and that BZD receptors do not significantly contribute to these effects.
Wierońska
Joanna M
JM
Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. wierons@if-pan.krakow.pl
Smiałowska
Maria
M
Brański
Piotr
P
Gasparini
Fabrizio
F
Kłodzińska
Aleksandra
A
Szewczyk
Bernadeta
B
Pałucha
Agnieszka
A
Chojnacka-Wójcik
Ewa
E
Pilc
Andrzej
A
D000679:Amygdala / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D008297:Male; D009478:Neuropeptide Y / Q000032:analysis / Q000096:biosynthesis*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D011963:Receptors, GABA-A / Q000032:analysis / Q000096:biosynthesis*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D009478:Neuropeptide Y; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine