Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, United States; Sarepta Therapeutics, Cambridge, MA, United States.
Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK, United States.
Neurotoxicology. 2021 Jan;82:82-88. doi: 10.1016/j.neuro.2020.11.007. Epub 2020 Nov 21.
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.
急性有机磷杀虫剂（OPs）中毒与抑郁和其他神经精神障碍有关。我们之前的研究报告称，用二异丙基氟磷酸酯（2.5mg/kg，sc）处理的成年雄性大鼠表现出急性胆碱能体征，随后在强迫游泳试验（一种衡量行为绝望的方法）中出现变化（不动性增加/游泳性减少），至少持续一个月。这项研究旨在评估强迫游泳试验中变化的进一步持续时间，直到 4 个月，并比较蔗糖偏好试验（一种快感缺失的测量方法）中的反应。成年雄性大鼠用载体（花生油，1ml/kg，sc）或 DFP（2.0、2.25 或 2.5mg/kg）处理，4 小时后处死，测量海马中的 OP 敏感丝氨酸水解酶（胆碱酯酶[ChE]、脂肪酸酰胺水解酶[FAAH]和单酰基甘油脂肪酶[MAGL]）。另外一些大鼠以类似的方式处理，并在 30 分钟至 6 天内评估急性毒性的功能体征，然后在给药后大约 1 周、1 个月和 4 个月评估运动活动、强迫游泳行为和蔗糖偏好。所有 DFP 剂量均引起丝氨酸水解酶抑制（ChE，92-96%；FAAH，46-63%；MAGL，26-33%）。所有 DFP 处理组在最初两周内体重减轻，高剂量组出现致死性。在所有 DFP 处理组中，在第一周内均出现不自主运动，但开始时间和恢复速度与剂量有关。在最高剂量（2.5mg/kg）后一周，步行明显减少，但没有其他明显的运动变化。2.25mg/kg DFP 使强迫游泳试验中动物的运动性降低和游泳性减少，在另外两个剂量组中，2 个时间点有这种现象。尽管水剥夺时间和 DFP 给药后时间会影响蔗糖偏好，但 DFP 处理没有主要影响。我们的结论是，强迫游泳试验（一种对不可避免的应激的行为绝望/应对机制的衡量）是急性 DFP 中毒的一种强烈而持久的神经行为后果，而蔗糖偏好（快感缺失的衡量标准和重度抑郁症的常见症状）不受影响。
