Abstracts

Rationale: Early exposure of the immature brain to benzodiazepines leads to enduring behavioral disturbances and morphologic alterations. There are however only limited data on effects of such treatment on brain excitability later in life. The present study aimed to examine whether early clonazepam (CZP) exposure results in enduring changes in seizure susceptibility. Methods: CZP in a dose of 1 mg/kg/day (suspension in saline) was administered intraperitoneally for five consecutive days beginning on postnatal day (P) 7. Seizure susceptibility was assessed using a model of pentylenetetrazole (PTZ) administration to both juvenile (P13-25) and adult animals. In juvenile rats, PTZ was administered in a threshold dose (50 mg/kg s.c.) at different intervals after treatment cessation (24h up to 14 days). Development of two types of convulsive seizures myoclonic and generalized tonic-clonic was registered. In adults (P90), PTZ (20mg/kg i.p.) was administered three times with 20-min intervals to rats with chronically implanted cortical electrodes and development and duration of rhythmic PTZ activity and myoclonic seizures was evaluated. Cortical excitability was determined based on electrically elicited cortical afterdischarges in juvenile and adolescent (P15-32) rats. Results: Early CZP exposure led to an enduring increase in PTZ sensitivity, which was seizure type specific. In juvenile rats, exposure to CZP sensitized rats to generalized tonic-clonic seizures, and an increased frequency of PTZ-induced spike-and-wave discharge episodes occurred in adults exposed to CZP early in life. In contrast, cortical excitability was transiently decreased shortly after CZP cessation and there was a tendency to suppress spread of epileptic activity to limbic structures. Conclusions: Our data demonstrated increased sensitivity to PTZ-induced seizures in animals exposed to CZP early in postnatal development. In contrast, transient decrease of excitability of sensorimotor cortex found in juvenile animals suggests rather delayed development of the sensorimotor cortex than increased resistance to epileptic seizures. This study was supported by grant No. P304/12/G069 of the Czech Science Foundation and Research Project RVO 67985823.