Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over 20 yr have elapsed since the end of the First Gulf War, yet approximately one-third of the veterans exhibit Gulf War Illness (GWI) symptoms, particularly depression and memory impairments. Exposure to organophosphate (OP) compounds is implicated for GWI development. The role of calcium (Ca2+) signaling in learning, memory, and mood is well established and disruptions in Ca2+ homeostasis are observed in many neurological disorders. However, the status of Ca2+ homeostasis in the development of GWI behavioral impairments is not known. Male Sprague-Dawley rats were exposed to OP agent diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c. 5 days), and at 6 mo post-DFP exposure, rats were subjected to behavioral assays for the determination of GWI neurological morbidities. Fura-2AM loaded acutely isolated hippocampal neurons were used for [Ca2+]i estimations. We observed chronic depressive symptoms and cognitive deficits in rats exposed to repeated low-dose DFP. The GWI rats also manifested elevations in hippocampal [Ca2+]i along with a significant increase in the number of neurons displaying these elevations. As Ca2+ is a major second-messenger molecule, such sustained increases in its levels could activate multiple signaling cascades and alter gene expression of proteins involved in synaptic plasticity and possibly underlie the neuronal injury and chronic morbidities in GWI.
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PMID:Chronic Neurological Morbidities and Elevated Hippocampal Calcium Levels in a DFP-Based Rat Model of Gulf War Illness. 2963 60

Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET's stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.
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PMID:Assessment of Ketamine and Its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness. 3262 72

Acute intoxication by organophosphorus anticholinesterases (OPs) has been associated with depression and other neuropsychiatric disorders. We previously reported that adult male rats treated with diisopropylfluorophosphate (2.5 mg/kg, sc) showed acute cholinergic signs followed by changes (increased immobility/decreased swimming) in the forced swim test (a measure of behavioral despair) for at least one month. This study was conducted to evaluate the further persistence of changes in the forced swim test out to 4 months and to compare responses in a sucrose preference test, a measure of anhedonia. Adult male rats were treated with vehicle (peanut oil, 1 mL/kg, sc) or DFP (2.0, 2.25 or 2.5 mg/kg) followed by sacrifice 4 h later for measurement of OP-sensitive serine hydrolases (cholinesterase [ChE], fatty acid amide hydrolase [FAAH], and monoacylglycerol lipase [MAGL]) in hippocampus. Additional rats were treated similarly and evaluated for functional signs of acute toxicity from 30 min to 6 days, and then motor activity, forced swim behavior and sucrose preference at approximately 1 week, 1 month and 4 months after dosing. All dosages of DFP elicited serine hydrolase inhibition (ChE, 92-96 %; FAAH, 46-63 %; MAGL, 26-33 %). Body weight was reduced in all DFP-treated groups during the first two weeks, and lethality was noted with the higher dosages. Involuntary movements were elicited in all DFP treatment groups during the first week, but both time of onset and rate of recovery were dose-related. There was a significant reduction in ambulation at one week after the highest dosage (2.5 mg/kg), but no other significant locomotor changes were noted. Immobility was increased and swimming was decreased in the forced swim test at all three time-points by 2.25 mg/kg DFP, and at 2 of 3 time-points by the other dosages. While length of water deprivation and time after DFP dosing affected sucrose preference, DFP treatment had no main effect. We conclude that the forced swim test (a measure of behavioral despair/coping mechanism for inescapable stress) is a robust and persistent neurobehavioral consequence of acute DFP intoxication while sucrose preference, a measure of anhedonia and a common symptom of major clinical depression, is not affected.
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PMID:Dose- and time-related effects of acute diisopropylfluorophosphate intoxication on forced swim behavior and sucrose preference in rats. 3323 45


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