Group I metabotropic glutamate receptors interfere in different ways with pentylenetetrazole seizures, kindling, and kindling-related learning deficits.
LY 367385 (mGluR1) and MPEP (mGluR5), which are group I metabotropic glutamate receptor (mGluR) antagonists, were used to investigate their effects on pentylenetetrazole (PTZ) seizures, kindling, and kindling-related learning deficits. Both substances showed anticonvulsant efficacy against seizures induced by lower doses of PTZ (40 mg/kg), but they were ineffective in counteracting seizures evoked by higher PTZ doses. When these substances were given in the course of kindling induction, LY significantly depressed the progression of kindled seizure severity. In contrast, MPEP was ineffective in this experiment. Treatment with either LY or MPEP did not modify the reaction to challenge dose of PTZ. Kindling results in a worsening of shuttle-box learning. LY improved shuttle-box learning when administered in the course of kindling development or when given prior to the learning experiment. This suggests protective and restorative effectiveness. In contrast, MPEP was only effective on the learning performance of kindled rats when given prior to the shuttle-box experiment, which demonstrates restorative effectiveness. Kindling is associated with an increase in glutamate binding. LY counteracted this increase whereas MPEP was ineffective. It was concluded that mGluR1 and mGluR5 play a specific role in the convulsive component of kindling. The beneficial action of the antagonists on kindling-induced impairments in shuttle-box learning may be associated with their effect on glutamatergic synaptic activity.
Nagaraja
Raghavendra Y
RY
Institute of Pharmacology and Toxicology, Faculty of Medicine, Otto-von-Guericke University, Leipziger Strasse 44, 39120, Magdeburg, Germany.
Grecksch
Gisela
G
Reymann
Klaus G
KG
Schroeder
Helmut
H
Becker
Axel
A
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004831:Epilepsies, Myoclonic / Q000139:chemically induced* / Q000517:prevention & control; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007696:Kindling, Neurologic / Q000187:drug effects / Q000473:pathology*; D007859:Learning Disabilities / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D010433:Pentylenetetrazole / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D001565:Benzoates; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; D005998:Glycine; D010433:Pentylenetetrazole