Neonatal N-(-2-Chloroethyl)-N-ethyl-2-Bromobenzylamine (DSP-4) Treatment Modifies the Vulnerability to Phenobarbital-and Ethanol-Evoked Sedative-Hypnotic Effects in Adult Rats
To study the influence of the central noradrenergic system on sensitivity to sedative-hypnotic effects mediated by the aminobutyric acid (GABA) system, intact rats were contrasted with rats in which noradrenergic nerves were largely destroyed shortly after birth with the neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine; 50 mg/kg sc x2, P1 and P3]. At 10 weeks, loss of the righting reflex (LORR) was used as an index to study the acute sedative-hypnotic effects of phenobarbital (100 mg/kg ip) and ethanol (4 g/kg ip, 25% v/v). Additionally, GABA concentration in the medial prefrontal cortex (PFC), hippocampus, cerebellum and brainstem was estimated by an HPLC/ED method. Neonatal DSP-4 treatment diminished the sedative-hypnotic effects of both phenobarbital and ethanol in adult rats. While the endogenous GABA content in the PFC, hippocampus, brainstem and cerebellum of DSP-4-treated rats was not altered, phenobarbital significantly decreased GABA content of both intact and DSP-4-lesioned rats by ∼40% in the hippocampus and by ∼20% in other brain regions at 1 h. Ethanol reduced GABA content by ∼15-30% but only in the hippocampus and brainstem of both intact and lesioned rats. These findings indicate that the noradrenergic system exerts a prominent influence on sedative-hypnotics acting via GABAergic systems in the brain without directly altering GABA levels in the brain.
Bortel, Aleksandra; Słomian, Lucyna; Nitka, Dariusz; Świerszcz, Michał; Jaksz, Mirella; Adamus-Sitkiewicz, Beata; Nowak, Przemysław; Jośko, Jadwiga; Kostrzewa, Richard M.; and Brus, Ryszard. 2008. Neonatal N-(-2-Chloroethyl)-N-ethyl-2-Bromobenzylamine (DSP-4) Treatment Modifies the Vulnerability to Phenobarbital-and Ethanol-Evoked Sedative-Hypnotic Effects in Adult Rats. Pharmacological Reports. Vol.60(3). 331-338. http://if-pan.krakow.pl/pjp/pdf/2008/3_331.pdf PMID: 18622057 ISSN: 1734-1140