Developmental and neurochemical effects of early postnatal exposure to flumazenil in female and male mice

intrinsic dose-dependent properties that affect behaviour. At a high dose (50 mg/kg), it is anticonvulsant (Nutt and Cowen, 1982), but at low doses (10 mg /Kg), it has an anxiogenic action (File and Pellow, 1985). Flumazenil crosses the placental barrier and can easily and quickly pass through the blood-brain barrier (Lister, Greenblatt, Abernethy and File, 1984), thus potentially modifying the developing central nervous system (CNS) in the neonate. Several studies have shown that perinatal exposure to benzodiazepines can affect early development and adult behaviour (Alleva, Laviola, Tirrelli, and Bignami, 1985; Benton, Dalrymple-Alford, Brain and Grimm, 1985; Gai and Grimm, 1982; Brain, Ajarem and Petkov, 1987; Pankaj and Brain, 1991a). Perinatal flumazenil treatment in pregnant rats has produced effects on emotivity-related behaviours of adult offspring (Fernández-Teruel, Driscoll, Escorihuela, Tobeña and Battig, 1993). Administration of this benzodiazepine antagonist to pregnant dams of a selected line of rats bred for poor acquisition of shuttle box performance, improved this task in adult subjects (Ferré, Escorihuela, Tobeña and Fernandez-Teruel, 1996). The authors argued that this effect could be due to a reduction of anxiety or to an improvement of memory in those animals. On the other hand, in a recent study, flumazenil did not produce a significant effect on rat pup ultrasonic vocalisation (Olivier, Molewijt, Van-Oorschot, Van-der-Heyden, Ronken and Mos,1998). G rimm, McAllister, Brain and Benton (1984) assessed the utility of the posture analysis in mice to assess how preand early p o s t n atal ex p o s u re to benzo d i a zepine influences later social interaction. It has been observed that pre and early post-natal ex p os u re to psych o a c t ive drugs influences later social intera c t i o n s . P re n at a l ly exposing males to diazepam ch a n ges their social beh aviour (Brain, Ajarem and Pe t kov, 1986). On the other hand, p re n atal administration of diffe rent benzo d i a zepine agonists and a n t agonists impairs the righting re fl ex as well as subsequently modifying social behaviour (Pankaj and Brain 1991a, b). Duri n g p o s t n atal development, dra m atic ch a n ges occur in the brain and its constituents. These disturbances may produce ch a n ges wh i ch a re accompanied by behav i o u ral ab n o rmalities. Changes in ch oDevelopmental and neurochemical effects of early postnatal exposure to flumazenil in female and male mice