Status epilepticus (SE) is the most common neurologic emergency in children. Both clinical and laboratory studies have demonstrated that SE in early life can cause brain damage and permanent behavioral abnormalities, trigger epileptogenesis, and interfere with normal brain development. In experimental rodent models, the consequences of seizures are dependent upon age, the model used, and seizure duration. In studies involving neonatal and infantile animals, the model used, experimental design, conditions during the experiment, and manipulation of animals can significantly affect the course of the experiments as well as the results obtained. Standardization of laboratory approaches, harmonization of scientific methodology, and improvement in data collection can improve the comparability of data among laboratories.

• Klíčová slova
• animal models, comorbidites, immature rodent, status epilepticus,
• MeSH
• laboratorní zvířata MeSH
• modely nemocí na zvířatech MeSH
• mozek MeSH
• status epilepticus * MeSH
• záchvaty MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

γ-aminobutyric acid (GABA) pathways play an important role in neuronal circuitry formation during early postnatal development. Our previous studies revealed an increased risk for adverse neurodevelopmental consequences in animals exposed to benzodiazepines, which enhance GABA inhibition via GABAA receptors. We reported that administration of the benzodiazepine clonazepam (CZP) during postnatal days 7-11 resulted in permanent behavioral alterations. However, the mechanisms underlying these changes are unknown. We hypothesized that early CZP exposure modifies development of glutamatergic receptors and their composition due to the tight developmental link between GABAergic functions and maturation of glutamatergic signaling. These changes may alter excitatory synapses, as well as neuronal connectivity and function of the neural network. We used quantitative real-time PCR and quantitative autoradiography to examine changes in NMDA and AMPA receptor composition and binding in response to CZP (1 mg/kg/day) administration for five consecutive days, beginning on P7. Brains were collected 48 h, 1 week, or 60 days after treatment cessation, and mRNA subunit expression was assessed in the hippocampus and sensorimotor cortex. A separate group of animals was used to determine binding to NMDA in different brain regions. Patterns of CZP-induced alterations in subunit mRNA expression were dependent on brain structure, interval after CZP cessation, and receptor subunit type. In the hippocampus, upregulation of GluN1, GluN3, and GluR2 subunit mRNA was observed at the 48-h interval, and GluN2A and GluR1 mRNA expression levels were higher 1 week after CZP cessation compared to controls, while GluN2B was downregulated. CZP exposure increased GluN3 and GluR2 subunit mRNA expression levels in the sensorimotor cortex 48 h after treatment cessation. GluA3 was higher 1 week after the CZP exposure, and GluN2A and GluA4 mRNA were significantly upregulated 2 months later. Expression of other subunits was not significantly different from that of the controls. NMDA receptor binding increased 1 week after the end of exposure in most hippocampal and cortical areas, including the sensorimotor cortex at the 48-h interval. CZP exposure decreased NMDA receptor binding in most evaluated hippocampal and cortical areas 2 months after the end of administration. Overall, early CZP exposure likely results in long-term glutamatergic receptor modulation that may affect synaptic development and function, potentially causing behavioral impairment.

• Klíčová slova
• AMPA receptor subunits, NMDA receptor autoradiography, NMDA receptor subunits, [3H] MK-801, benzodiazepine, clonazepam, mRNA expression, neonatal rat,
• Publikační typ
• časopisecké články MeSH

Social behavior represents an integral part of behavioral repertoire of rats particularly sensitive to pharmacological and environmental influences. The aim of the present study was to investigate whether early postnatal clonazepam (CZP) exposure can induce age-dependent changes related to expression of social behavior. The drug was administered from postnatal day (P) 7 until P11 at daily doses of 0.1, 0.5 and 1.0 mg/kg i.p. We designed three experiments to assess whether exposure to CZP affects social behavior in respect to the age of rats and the test circumstances, specifically their familiarity with test conditions during adolescence (P32), social behavior in juveniles and adolescents (P18-P42) and social behavior in a resident-intruder paradigm. The frequency and duration of a various patterns of social behavior related to play and social investigation not related to play were evaluated. The results showed that CZP postnatal exposure decreased social play behavior regardless of age and familiarity or unfamiliarity of experimental environment but did not affect the social investigation per se. When rats were confronted with an intruder in their home cages intense wrestling and inhibition of genital investigation were found. In conclusion, these findings show that short-term CZP postnatal exposure inhibits social play behavior and alters specific patterns of social behavior in an age and environment related manner.

• Klíčová slova
• benzodiazepines, clonazepam, development, rats, social behavior,
• Publikační typ
• časopisecké články MeSH

Clinical and experimental studies suggest possible risks associated with the repeated administration of benzodiazepines (BZDs) during the prenatal or early postnatal period on further development and behavior. In the present study, we assess short- and long-term effects of early exposure to clonazepam (CZP) on cognitive tasks. CZP (0.5 or 1.0 mg/kg/day) was administered from postnatal day (P)7 until P11, and animals were exposed to the following behavioral tests at different developmental stages: (1) a homing response (HR) test, which exploits the motivation of a rat pup to reach its home nest, was administered on P12, P15, P18 and P23 rats; (2) passive avoidance was tested in three trials (at 0, 2 and 24 h intervals) on P12, P15, P18, P25 and P32 rats; (3) within- and between-session habituation was tested in an open field (OF) at P70; and (4) a long-term memory (LTM) version of the Morris water maze (MWM) was tested at P80. A 1.0 mg/kg dose of CZP extended latency in the HR and decreased the number of correct responses when tested at P12 and P23. In the first trial of the passive avoidance test, latency to enter a dark compartment was shorter in the CZP-exposed rats. Both treated and control animals older than P15 learned the passive-avoidance response at the same rate. Irrespective of the treatments, all adult animals showed within-session habituation. Between-session habituation, however, was found only in the controls. With respect to the MWM test, all animals learned to reach the platform, but animals exposed to higher doses of CZP spent more time swimming in the first acquisition test. No difference between groups was found in a repeated acquisition test (10 and 40 days after the first acquisition test). The results of the present study show that even short-term exposure to CZP alters behavioral responsiveness in pre-weaning, juvenile and adult animals. Not only were changes observed on conventional cognitive tests in our study, but the changes also seem to be related to emotional/motivational responsiveness.

• Klíčová slova
• benzodiazepines, clonazepam, cognitive functions, development, rats,
• Publikační typ
• časopisecké články MeSH