Department of Functional Biology and Health Sciences, Faculty of Biology, University of Vigo, Vigo, Spain.
Department of Functional Biology and Health Sciences, Faculty of Biology, University of Vigo, Vigo, Spain.
Pestic Biochem Physiol. 2023 Jun;193:105433. doi: 10.1016/j.pestbp.2023.105433. Epub 2023 Apr 23.
The main objective of this study was to evaluate the effects and possible mechanisms of action of glyphosate and a glyphosate-based herbicide (GBH) on dopaminergic neurotransmission in the rat striatum. Acute exposure to glyphosate or GBH, administered by systemic (75 or 150 mg/kg, i.p.) or intrastriatal (1, 5, or 10 mM for 1 h) routes, produced significant concentration-dependent increases in dopamine release measured in vivo by cerebral microdialysis coupled to HPLC with electrochemical detection. Systemic administration of glyphosate also significantly impaired motor control and decreased striatal acetylcholinesterase activity and antioxidant capacity. At least two mechanisms can be proposed to explain the glyphosate-induced increases in extracellular dopamine levels: increased exocytotic dopamine release from synaptic vesicles or inhibition of dopamine transporter (DAT). Thus, we investigated the effects of intrastriatal administration of glyphosate (5 mM) in animals pretreated with tetrodotoxin (TTX) or reserpine. It was observed that TTX (10 or 20 μM) had no significant effect on glyphosate-induced dopamine release, while reserpine (10 mg/kg i.p) partially but significantly reduced the dopamine release. When glyphosate was coinfused with nomifensine (50 μM), the increase in dopamine levels was significantly higher than that observed with glyphosate or nomifensine alone. So, two possible hypotheses could explain this additive effect: both glyphosate and nomifensine act through different mechanisms at the dopaminergic terminals to increase dopamine levels; or both nomifensine and glyphosate act on DAT, with glyphosate simultaneously inhibiting reuptake and stimulating dopamine release by reversing the DAT function. Future research is needed to determine the effects of this pesticide at environmentally relevant doses.
本研究的主要目的是评估草甘膦和草甘膦基除草剂（GBH）对大鼠纹状体多巴胺能神经传递的影响及其可能的作用机制。急性腹腔内（75 或 150mg/kg）或纹状体内（1、5 或 10mM，1 小时）给予草甘膦或 GBH 会导致多巴胺释放显著增加，这是通过与电化学检测相结合的 HPLC 进行的脑微透析在体内测量的。草甘膦的全身给药还显著损害了运动控制并降低了纹状体乙酰胆碱酯酶活性和抗氧化能力。至少可以提出两种机制来解释草甘膦诱导的细胞外多巴胺水平升高：来自突触小泡的囊泡胞吐作用增加或多巴胺转运蛋白（DAT）抑制。因此，我们研究了在预先用河豚毒素（TTX）或利血平预处理的动物中纹状体内给予草甘膦（5mM）的影响。观察到 TTX（10 或 20μM）对草甘膦诱导的多巴胺释放没有显著影响，而利血平（10mg/kg 腹腔内注射）部分但显著降低了多巴胺释放。当草甘膦与诺米芬新（50μM）共输注时，多巴胺水平的升高明显高于单独使用草甘膦或诺米芬新时的升高。因此，有两种可能的假设可以解释这种相加效应：草甘膦和诺米芬新都通过不同的机制作用于多巴胺能末梢来增加多巴胺水平；或者诺米芬新和草甘膦都作用于 DAT，草甘膦通过逆转 DAT 功能同时抑制再摄取并刺激多巴胺释放。需要进一步研究以确定这种农药在环境相关剂量下的影响。
