Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime

Abstract

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.

Inducible nitric oxide synthase inhibitor, 1400W, mitigates DFP-induced long-term neurotoxicity in the rat model

“…None of these MWM studies did pre-exposure baseline tests as we did in this study. It is plausible that the prior learning may have impacted the learning and memory at 10–16 and 28–34 days post-exposure in this study in contrast to the published literature (Brewer et al, 2015, 2013; Prendergast et al, 1997). On an off note, the animals in our study were also subjected to other behavioral tests which may have interfered with MWM performance or vice versa.…”

“…In this study, even though we observed increased epileptiform activity, intensely stained S-100β in reactive astrocytes, proinflammatory cytokines, and hippocampal neurodegeneration, we did not observe significant differences in learning and short-term memory in the MWM when the animals were tested between 10–16 and 28–34 days post- exposure. Previous studies reported the impact of acute exposure of DFP on cognition in the MWM only after 4 or 12 weeks of exposure (Brewer et al, 2015, 2013). In a chronic exposure DFP study, 35 days after the first DFP exposure affected spatial learning (Prendergast et al, 1997).…”

Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning

“…Treatment groups and the respective administered agents are depicted in Table 1 . Doses of DFP and SOC were selected based on the literature 9 , 27 – 29 . DFP was administered at 3 mg/kg as single, intravenous bolus dose to simulate an acutely toxic one-time exposure.…”

The Effect of Naltrexone on Memory Deficit Followed by Electroconvulsive Therapy: A Randomized, Double-Blind, Placebo-Controlled Trial

“…Morphine-induced impairment may be the result of the effect of mu-opioid receptors, because the action of opioids might be inhibited by mu-opioid receptor antagonists (12). Lately, studies working on the impact of administration of opioid antagonists, such as naloxone and naltrexone, on memory expansion in lab animals have been performed (13,14). memory seems to be the result of augmenting GluA1-S845 phosphorylation-dependent AMPAR trafficking (16).…”