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 approximately 40% in the hippocampus and by approximately 20% in other brain regions at 1 h. Ethanol reduced GABA content by approximately 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
A
Department of Pharmacology, Medical University of Silesia, H. Jordana 38, PL 41-808 Zabrze, Poland.
Słomian
Lucyna
L
Nitka
Dariusz
D
Swierszcz
Michał
M
Jaksz
Mirella
M
Adamus-Sitkiewicz
Beata
B
Nowak
Przemysław
P
Jośko
Jadwiga
J
Kostrzewa
Richard M
RM
Brus
Ryszard
R
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001596:Benzylamines / Q000008:administration & dosage / Q000494:pharmacology*; D001679:Biogenic Amines / Q000378:metabolism; D001933:Brain Stem / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D010634:Phenobarbital / Q000008:administration & dosage / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D001596:Benzylamines; D001679:Biogenic Amines; D002492:Central Nervous System Depressants; D006993:Hypnotics and Sedatives; D014179:Neurotransmitter Uptake Inhibitors; D000431:Ethanol; D008734:Methoxyhydroxyphenylglycol; D005680:gamma-Aminobutyric Acid; C012102:DSP 4; D004298:Dopamine; D010634:Phenobarbital