ABSTRACT
Potentiation of GABAergic inhibition is a mechanism of action of many antiepileptic drugs. The potential use of an agonist of GABAA receptors, muscimol, as an antiepileptic drug was studied in immature rats by assessing anticonvulsant activity and side effects on motor activities. Anticonvulsant action was tested in two models of seizures (pentetrazol-induced convulsions and cortical epileptic afterdischarges). Off target effect on motor performance was assessed in a battery of tests and in the open field in three age groups (12-, 18- and 25-day-old rats). Muscimol was administered in doses from 0.1 to 1mg/kg i.p. Only the 1 mg/kg dose exhibited marked anticonvulsant effect against pentetrazol-induced convulsions in 12- and 18-day-old rats, proconvulsant effect was observed in the second model in 18- and 25-day-old rats as prolongation of afterdischarges. Even the 0.5 mg/kg dose suppressed spontaneous locomotion and heavily compromised motor performance. The effect on motor activity was marked in the youngest group and decreased with age. Due to the low anticonvulsant potency and serious side effects, systemic administration of a competitive agonist of GABAA receptors in immature animals is not a promising strategy for new anticonvulsants.
Subject(s)
Anticonvulsants/pharmacology , Brain/drug effects , GABA-A Receptor Agonists/pharmacology , Motor Activity/drug effects , Muscimol/pharmacology , Seizures/drug therapy , Age Factors , Animals , Brain/growth & development , Brain/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Electroencephalography , Epilepsy/drug therapy , Epilepsy/physiopathology , Exploratory Behavior/drug effects , Exploratory Behavior/physiology , Male , Motor Activity/physiology , Neuropsychological Tests , Pentylenetetrazole , Rats, Wistar , Seizures/physiopathology , Severity of Illness IndexABSTRACT
Possible anticonvulsant action of GABAB receptor positive allosteric modulator CGP7930 was studied in cortical epileptic afterdischarges (ADs) in rat pups 12, 18, and 25 days old. Afterdischarges were induced by six series of stimulation of sensorimotor cortex, and CGP7930 (20 or 40 mg/kgi.p.) was administered after the first AD. In addition, the effects of CGP7930 on sensorimotor performance and behavior in open field and elevated plus maze were assessed. CGP7930 decreased duration of ADs in 12-day-old but not in older rats. Motor phenomena (movements accompanying stimulation and clonic seizures) were not changed. CGP7930 only moderately affected sensorimotor performance, altered slightly spontaneous behavior in the open field, and did not influence behavior in the elevated plus maze in terms of an adaptive form of learning or anxiety-like behavior. Marked anticonvulsant action with subtle deficits in sensorimotor performance in 12-day-old rats suggests a possible use of CGP7930 as an age-specific anticonvulsant.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Exploratory Behavior/drug effects , Motor Activity/drug effects , Phenols/therapeutic use , Psychomotor Performance/drug effects , Age Factors , Analysis of Variance , Animals , Animals, Newborn , Anticonvulsants/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Electric Stimulation/adverse effects , Epilepsy/etiology , Grooming/drug effects , Male , Maze Learning/drug effects , Phenols/pharmacology , Rats , Rats, Wistar , Reaction Time/drug effects , Rotarod Performance Test , Sensory Gating/drug effectsABSTRACT
High doses of mGluR5 antagonists have anticonvulsant effects in multiple seizure models in both adult and immature animals. Data on potential behavioral effects in immature animals are very scarce. The present study investigated whether an antagonist of mGluR5 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) in doses proven to be anticonvulsant affects behavior in immature rats. Animals aged 12, 18 and 25 days received MTEP in doses of 20 and 40 mg/kg i. p. The sensorimotor performance was tested at 15 and 60 min after dosing. Locomotor-exploratory behavior was tested at 20 and 65 min after dosing. An elevated plus maze was used to examine an adaptive form of learning and anxiety-like behavior in 18- and 25-day-old rats at 15, 60 min and 24h. MTEP slightly affected sensorimotor performance, regardless of age. In the open field test, MTEP decreased transiently locomotor-exploratory behavior but did not affect the habituation - a simple form of nonassociative learning. In the elevated plus maze, the drug did not impair transfer latency, an indicator of an adaptive form of learning and memory. An anxiolytic-like effect was observed at 60 min after drug administration. In conclusion, no severe impairment was observed after high anticonvulsant doses of mGlu5 antagonist MTEP in immature animals.
Subject(s)
Behavior, Animal/drug effects , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Thiazoles/pharmacology , Aging/psychology , Animals , Anxiety/psychology , Exploratory Behavior/drug effects , Grooming/drug effects , Learning/drug effects , Male , Memory/drug effects , Motor Skills/drug effects , Psychomotor Performance/drug effects , Rats , Rats, Wistar , Receptor, Metabotropic Glutamate 5 , Reflex/drug effects , Space Perception/drug effectsABSTRACT
Antagonists of group I of metabotropic glutamate receptors (mGluRs) exhibit anticonvulsant as well as anxiolytic action in adult rodents. Therefore, we started to study these effects in developing rats. Motor seizures induced by pentylenetetrazol (PTZ) and cortical epileptic afterdischarges (CxADs) elicited by electrical stimulation were used in immature rats. High doses of antagonists were needed to demonstrate anticonvulsant effects. Antagonist of mGluR1 AIDA [(R,S)-1-aminoindan-1,5-dicarboxylic acid] suppressed the tonic phase of PTZ-induced generalized tonic-clonic seizures in 7-, 12-, and 18-day-old rats, but not in 25-day-old rats. No significant effect of AIDA against CxADs was found. Antagonists of mGluR5-MPEP [2-methyl-6-(phenylethynyl)-pyridine] and MTEP [3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine] exhibited the same effect against PTZ-induced seizures as AIDA. In addition, they exhibited an anticonvulsant action against CxADs in 12- and 18-day-old rats. No drug compromised motor performance. Anxiolytic action of all three antagonists was demonstrated in light/dark box or in elevated plus maze tests. Homing reaction was used as an age-appropriate test of learning. AIDA did not affect homing, whereas the highest dose of MPEP compromised this behavior in 12- and partially in 18-day-old rats. The three antagonists possess age-dependent anticonvulsant as well as anxiolytic action, with minimal negative side effects.
