title: Long-term cognitive deficits accompanied by reduced neurogenesis after soman poisoning.
abstract: To date, treatment of organophosphate (OP) poisoning shows several shortcomings, and OP-victims might suffer from lasting cognitive deficits and sleep-wake disturbances. In the present study, long-term effects of soman poisoning on learning ability, memory and neurogenesis were investigated in rats, treated with the anticholinergic atropine and the oxime HI-6 for reactivation of soman-inhibited acetylcholinesterase. We also investigated whether sub-chronic treatment with the reported neurogenesis enhancer olanzapine would stimulate neurogenesis and possibly normalize the anticipated long-term deleterious effects of soman intoxication. Animals were treated with HI-6 (125 mg/kg i.p.), followed after 30 min by soman (200 microg/kg s.c.) and atropine sulphate (16 mg/kg i.m.) 1 min thereafter. Soman poisoning led to an elevation of extracellular acetylcholine levels to 1500% over baseline values as assessed by striatal microdialysis. Brain acetylcholinesterase was inhibited over 95%. This was accompanied by short recurrent seizures lasting for 40 min. Osmotic minipumps releasing olanzapine (7.5 mg/kg/day) or vehicle were subcutaneously implanted 24 h post-intoxication. After drug delivery for 4 weeks, newborn cells were BrdU labeled. Learning and memory performance were assessed 8 weeks after soman poisoning, followed by analysis of surviving newborn cells (BrdU) and neurogenesis (doublecortin, DCX). Eight weeks after soman-intoxication a significantly impaired learning ability was found that was paralleled by significantly lower numbers of DCX-positive cells but no changes in the number of BrdU-labeled cells. Apparently, the present Olanzapine regime was ineffective. We conclude that soman poisoning has long lasting effects on learning ability, a finding that was accompanied by impaired neurogenesis. Although we confirm a correlation between impaired neurogenesis and cognitive deficits, establishing the true causal relationship between these processes in OP exposed animals awaits future research.
authors.affiliation: TNO Defence, Security and Safety, BU Biological and Chemical Protection, Rijswijk, The Netherlands. marloes.joosen@tno.nl
authors.forename: Marloes J A
authors.initials: MJ
authors.lastname: Joosen
authors.forename: Edwin
authors.initials: E
authors.lastname: Jousma
authors.forename: Tom M
authors.initials: TM
authors.lastname: van den Boom
authors.forename: Willem C
authors.initials: WC
authors.lastname: Kuijpers
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lucassen
authors.forename: Herman P M
authors.initials: HP
authors.lastname: van Helden
mesh_terms: D000109:Acetylcholine / Q000032:analysis*; D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D003342:Corpus Striatum / Q000737:chemistry; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D000077152:Olanzapine; D010091:Oximes; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced; D012999:Soman / Q000506:poisoning*
chemical_list: D002801:Cholinesterase Reactivators; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D010091:Oximes; D011726:Pyridinium Compounds; D001569:Benzodiazepines; D001285:Atropine; D012999:Soman; D000110:Acetylcholinesterase; C022870:asoxime chloride; D000077152:Olanzapine; D000109:Acetylcholine