Abstracts

Rationale: Organophosphate (OP) compounds include pesticides and nerve agents that elicit lethal toxicity by inhibiting acetylcholinesterase (AChE) which leads to an acute cholinergic syndrome that evolves into status epilepticus (SE). There is a growing concern that OP agents could be used to cause mass civilian casualties. Similar to the survivors of SE, OP toxicity is associated with neurobehavioral deficits including mood changes, depression, and memory impairments. In this study we investigated whether animals surviving lethal OP exposure exhibited long-term neurological impairments, using diisopropyl fluorophosphate (DFP), an OP agent used in civilian laboratories to mimic effects of nerve agent exposure.Methods: Male Sprague-Dawley rats (250-300g) were injected with DFP (4 mg/kg, s.c). One minute following DFP injection, rats were injected with atropine sulfate (2 mg/kg, i.p) and 2-PAM (25 mg/kg, i.m). Rats exhibited cholinergic crisis, including the occurrence of status epilepticus. Seizures were stopped with three injections of diazepam (5 mg/kg, i.p) plus 2-PAM at 1, 3 and 5-hr following the onset of SE. Approximately 4-months following DFP exposure the rats were screened for depressive symptoms using forced swim test (FST), sucrose preference test (SPT) and elevated plus maze (EPM). Cognitive deficits were investigated using the novel object recognition test (NORT).Results: DFP-SE rats subjected to FST exhibited increased immobility time (83.03±8.5s, n= 5) indicative of a despair-like state that was significantly higher than age matched controls (35.46±3.8s, n= 5, p< 0.05). In the SPT, DFP rats consumed significantly less sucrose water indicating anhedonia-like condition (58.40±5.9% sucrose preference in DFP rats Vs 82.66±6.5% in control rats). DFP rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the EPM (time in open arm: 18.9±4.5% in controls Vs 4.2±1.5% in DFP rats). In NORT, DFP SE rats exhibited a discrimination ratio of 0.28±0.09 indicative of impaired recognition memory that was significantly lower compared to age matched control rats (0.76±0.07, n= 5, p< 0.05).Conclusions: Here we observed depression-like symptoms and cognitive deficits in rats surviving severe OP exposure. Evidence from the civilian population indicates that repeated exposure to OP insecticides or a single acute exposure to nerve agents can lead to chronic neurological morbidities. Approximately 35% of soldiers deployed in the 1991 Persian Gulf War suffer from chronic multi-symptom illnesses characterized by depression and cognitive deficits, which is thought to be due to OP/ nerve agent exposure during deployment. SE is also known to produce cognitive deficits by affecting the hippocampus and changing neuronal networks in the brain. This DFP model mimics both the acute hyper-cholinergic response and exhibits chronic behavioral impairments and cognitive deficits. It is being used to identify molecular mechanisms and screen novel pharmacological agents for effective treatment of these co-morbid disorders.