Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime.
Humans and rats poisoned with sarin develop chronic neurological disabilities that are not prevented with standardized antidotal therapy. We hypothesized that rats poisoned with the sarin analogue diisopropylfluorophosphate (DFP) and resuscitated with atropine and pralidoxime would have long-term memory deficits that were preventable with naltrexone treatment. Long Evans rats (250-275 g) were randomized to: DFP (N = 8): single subcutaneous (SC) injection of DFP (5 mg/kg). Treatment (N = 9): DFP (5 mg/kg) followed by chronic naltrexone (5 mg/kg/day × 12 weeks). Control (N = 12): single SC injection of isopropyl alcohol, (DFP vehicle) followed by chronic naltrexone (5 mg/kg/day). If toxicity developed after injection, antidotal therapy was initiated with atropine (2 mg/kg) and pralidoxime (25 mg/kg) and repeated as needed. After 12 weeks, rats underwent testing for place learning (acquisition) across 5 days of training using the Morris Water Maze. On day 6 a memory retention test was performed. Statistical analysis was performed using IBM SPSS Statistics. Rats receiving DFP rapidly developed toxicity requiring antidotal rescue. No differences in acquisition were seen between the DFP vs. DFP + naltrexone rats. During memory testing, DFP-poisoned rats spent significantly less time (29.4 ± 2.11 versus 38.5 ± 2.5 s, p < 0.05) and traveled less distance (267 ± 24.6 versus 370 ± 27.5 cm, p < 0.05) in the target quadrant compared to the treatment group. Treatment rats performed as well as control rats (p > 0.05) on the test for memory retention. Poisoning with DFP induced impaired memory retention. Deficits were not prevented by acute rescue with atropine and pralidoxime. Chronic naltrexone treatment led to preserved memory after DFP poisoning.
Department of Emergency Medicine, Brody School of Medicine at East Carolina University, 600 Moye Boulevard, Room 3ED311, Greenville, NC, 27834, USA. brewerk@ecu.edu.
Kori L
KL
Brewer
Department of Psychology, East Carolina University, Greenville, NC, USA.
Tuan
T
Tran
Department of Emergency Medicine, Brody School of Medicine at East Carolina University, 600 Moye Boulevard, Room 3ED311, Greenville, NC, 27834, USA.
William J
WJ
Meggs
D000818:Animals; D001285:Atropine / Q000008:administration & dosage*; D005260:Female; D007531:Isoflurophate / Q000506:poisoning*; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control*; D009271:Naltrexone / Q000627:therapeutic use*; D011220:Pralidoxime Compounds / Q000008:administration & dosage*; D051381:Rats; D020318:Rats, Long-Evans
D011220:Pralidoxime Compounds; D007531:Isoflurophate; D009271:Naltrexone; D001285:Atropine; C028797:pralidoxime
Diisopropylflurophosphate; Memory deficits; Naltrexone; Nerve agents; Sarin