Early neurobehavioral and neurochemical alterations in rats prenatally exposed to imipramine.

Pregnant CD rats were treated subcutaneously with 0, 5 or 10 mg/kg/day of imipramine (IMI) on days 8-20 of gestation. Behavioral and neurochemical endpoints were measured at different postnatal days (PND). Three behavioral tests were conducted: negative geotaxis on PNDs 7-9; auditory startle habituation (ASH) on PNDs 14, 16 and 18; locomotor activity before and after intraperitoneal (i.p.) injection of saline or 0.5 mg/kg d-amphetamine on PND 21. Catecholamine levels, B-adrenergic and muscarinic cholinergic binding were measured on PND 1 and in PND 21 rats 3 hours after challenge. Maternal weight gained during the dosing period was decreased in a dose-related manner, but there were no dose-related differences in offspring body weights. On PND 7, low-dose males turned significantly sooner in negative geotaxic testing, and more high-dose males successfully turned (94%) than did controls (61%). A significant reduction in ASH amplitude was found only in males from the low-dose group on PND 18. IMI-exposed males tended to be more active prior to and following amphetamine challenge. On PND 1, male offspring from the low-dose group showed a 65% reduction in B-adrenergic receptor binding and a trend toward increased brain epinephrine (EPI) levels. On PND 21, no consistent dose-related receptor binding changes were observed. Cortical levels of EPI, however, tended to be higher in treated males and high-dose females challenged with d-amphetamine. These same rats also showed a marked elevation in locomotor activity following challenge with d-amphetamine. Thus, prenatal IMI exposure appeared to alter functional development of the central adrenergic systems in a complex manner, but one consistent with changes noted in both neurochemical and behavioral endpoints.