Abstract
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.
Highlights
Experiences during early life critically affect the development of the brain
The criteria for correct homing response (HR) were achieved in 75% of the P12 and P15 rats, and in 100% of the P18 and P23 animals
Results of the present study indicate that even short lasting exposure of postnatal rats to CZP in an anticonvulsant dose range leads to mild alterations of behavioral responsiveness in cognitiverelated behavior in immature, juvenile and adult animals
Summary
Experiences during early life critically affect the development of the brain. The ultimate effect of early life experiences can contribute to either risk or resilience to neuropsychiatric conditions later in life. Enduring cognitive alterations following the termination of exposure to BZDs is not documented in adult patients (for review Lader, 2011). Sparse developmental studies suggest that exposure of the immature brain to BZDs can result in cognitive alterations lasting long after the cessation of BZD exposure. In most published studies, animals are exposed to BZDs through several developmental stages, beginning in the prenatal period. In many of these studies, exposure duration is extremely long, lasting through gestation
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