Biologia, Bratislava, 55/Suppl. 8: 9-13, 2000.

ISSN 0006-3088 (Biologia). ISSN 1335-6399 (Biologia. Section Cellular and Molecular Biology).

 

Full Paper

Timing of drug exposure during neonatal ontogeny and expression of brain maldevelopment in the adult rat.

 

Olga Benesova* & Hana Tejkalova

Prague Psychiatric Center, CZ-18103 Prague 8, Ustavni 91, Czech Republic; tel.: ++ 420 2 66003160; fax: ++ 420 2 66003134; e-mail: benesova@pcp.lf3.cuni.cz

* Corresponding author

Received September 19, 2000 / Accepted: October 24, 2000

 

Abstract

The risk of neurodevelopmental disturbances was studied in regard to three drugs used in perinatal therapy of risk pregnancies and risk neonates: dexamethasone (DEX), diazepam (DIA) and indomethacin (INDO). Model experiments were carried out in rats, strain Wistar, which were injected with the drugs tested in clinically relevant doses (DEX 1 mg/kg, DIA 5 mg/kg, INDO 2 mg/kg, s.c.) either on postnatal days 4&5 (PD:4-5; ontogenic model of human foetus/preterm neonate of 7-month gestational age) or on postnatal days 9&10 (PD:9-10; ontogenic model of full-term newborn). Rats were followed up during development (weight, maturation) and in adulthood (age 3-9 months) using tests of behaviour (open field), memory (social recognition), pain sensitivity (tail flick, plantar test), seizure susceptibility (bicuculline-induced EEG rhythmic activity), ability of reproduction and brain neurobiochemical analysis. - Adult rats of all three groups (DEX, DIA, INDO) revealed immune deficiency, but only when drugs were applied on PD:9-10, indicating potential vulnerability of this more advanced phase of ontogeny for immune function development Defects of memory and reproduction appeared following DIA administration on PD:4-5, and following DEX administration at both ontogenic levels. Special disturbances of adult behavioural reactivity were found in DIA rats (increased seizure susceptibility) and in INDO rats (pain hypersensitivity) when the drugs tested were applied on PD:9-10. It is evident that not only the drug itself, but also the timing of its administration during perinatal ontogeny is decisive for neurodevelopmental damage and its expression in adulthood.

 

Key words: brain maldevelopment, perinatal pharmacotherapy, drug teratogenicity, dexamethasone, diazepam, indomethacin.