title: Brain norepinephrine reductions in soman-intoxicated rats: association with convulsions and AChE inhibition, time course, and relation to other monoamines.
abstract: The organophosphate chemical nerve agent, soman, causes convulsions, neuropathology, and, ultimately, death. A major problem in treating soman intoxication is that peripherally acting pharmacological agents which prevent death do not prevent seizures. Although a primary cause of these symptoms is the excess of acetylcholine which follows acetylcholinesterase (AChE) inhibition, centrally acting muscarinic blockers, such as atropine, alleviate, but do not block, the convulsive actions of soman. Moreover, there is a relatively weak relationship between CNS reductions of AChE and the incidence of convulsions. There is evidence suggesting that soman intoxication stimulates the release of norepinephrine (NE) in the brain. Recent evidence has implicated NE in the induction and/or maintenance of seizures. Thus, in the present study the relations among soman-induced convulsions, AChE inhibition, and brain NE and other monoamine changes were examined. The time course of brain NE recovery was also determined. Rats were injected (im) with a single dose (78 micrograms/kg) of soman. At this dose 68% of the injected rats developed convulsions. Both convulsive and nonconvulsive rats were sacrificed between 1 and 96 h following soman injection and NE levels in the rostral forebrain and olfactory bulb were determined by HPLC with electrochemical detection. In all convulsive rats NE levels declined substantially. Forebrain NE levels were decreased by 50% at 1 h and 70% at 2 h following soman injection. Recovery of NE began at 8 h and was complete by 96 h following soman administration. Although nonconvulsive rats showed other signs of intoxication, NE levels in these rats were unchanged. Dopamine (DA) and serotonin (5-HT) levels were not significantly affected in either convulsive or nonconvulsive rats. However, 5-hydroxyindoleacetic acid, the major metabolite of 5-HT, and homovanillic acid and 3,4-dihydroxyphenylacetic acid, the two major metabolites of DA, were increased significantly in the forebrain of convulsive, but not nonconvulsive rats, indicating an increase in 5-HT and DA turnover. However, in contrast to the abrupt decline in NE, these increases in DA and 5-HT metabolites were slow and progressive. Taken together, the present results and other recent findings suggest that rapid, sustained NE release could play a role in the induction and/or maintenance of soman-induced convulsions, whereas increased release of 5-HT and DA may be a consequence of seizures. Further investigation of the role of NE in soman-induced convulsions may lead to improved treatment of soman intoxication and a better understanding of the role of NE in other forms of seizures, including human epilepsy.
authors.affiliation: Department of Anatomy and Cell Biology, University of Cincinnati College of Medicine, Ohio 45267-0521.
authors.forename: M M
authors.initials: MM
authors.lastname: el-Etri
authors.forename: W T
authors.initials: WT
authors.lastname: Nickell
authors.forename: M
authors.initials: M
authors.lastname: Ennis
authors.forename: K A
authors.initials: KA
authors.lastname: Skau
authors.forename: M T
authors.initials: MT
authors.lastname: Shipley
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001679:Biogenic Amines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced*; D012999:Soman / Q000506:poisoning*; D013997:Time Factors
chemical_list: D001679:Biogenic Amines; D002800:Cholinesterase Inhibitors; D015102:3,4-Dihydroxyphenylacetic Acid; D012999:Soman; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid