Evaluation of cognitive and biochemical effects of low-level exposure to sarin in rhesus and African green monkeys.
We investigated the potential of low-level exposures to the chemical warfare nerve agent, sarin, to produce adverse effects. Rhesus (Macaca mulatta) and African green monkeys (Chlorocebus acthiops) were trained on a serial probe recognition (SPR) task before IM administration of a low-level concentration (5.87 microg/kg or 2.93 microg/kg) of sarin. Blood was sampled before agent administration and at various times following administration. Sarin administration did not disrupt performance on the SPR task in either species. Major dependent measures characterizing performance (accuracy, number of completed trials per session, average choice response time) were largely unaffected on the day sarin was administered as well as on subsequent testing sessions occurring over several weeks following administration. Analyses of red blood cell (RBC) and plasma samples revealed that sarin administration produced a substantial degree of inhibition of circulating acetylcholinesterase (AChE) in RBC fractions and butyrylcholinesterase (BChE) in plasma fractions, which only slowly recovered. In this regard, AChE activity was inhibited to a greater extent than BChE activity. Blood samples were also evaluated for regenerated sarin, which was found in RBC and plasma fractions in both species and showed orderly elimination functions. More sarin was regenerated from RBC fractions than from plasma fractions. Elimination of regenerated sarin was much slower in RBC than plasma and exceeded the expected time of AChE aging, suggesting the presence of additional sarin binding sites. In general, effects were similar in both species. Taken together, our results show that while the concentrations of sarin administered were clearly biochemically active, they were below those that are required to produce a disruption of behavioral performance.
Genovese
Raymond F
RF
Division of Psychiatry and Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA. Raymond.Genovese@US.ARMY.MIL
Oubre
John L
JL
Jakubowski
E Michael
EM
Fleming
Patrick J
PJ
Saxena
Ashima
A
Rockwood
Gary A
GA
Tipparaju
Prasanthi
P
Willmore
Catherine B
CB
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000097:blood; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D002522:Chlorocebus aethiops; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood; D003071:Cognition / Q000187:drug effects; D005260:Female; D008253:Macaca mulatta; D008297:Male; D012524:Sarin / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*
D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D012524:Sarin; D002091:Butyrylcholinesterase; D002802:Cholinesterases