Chronic unpredictable stress influenced the behavioral but not the neurodegenerative impact of paraquat

Abstract

The impact of psychological stressors on the progression of motor and non-motor disturbances observed in Parkinson's disease (PD) has received little attention. Given that PD likely results from many different environmental “hits”, we were interested in whether a chronic unpredictable stressor regimen would act additively or possibly even synergistically to augment the impact of the toxicant, paraquat, which has previously been linked to PD. Our findings support the contention that paraquat itself acted as a systemic stressor, with the pesticide increasing plasma corticosterone, as well as altering glucocorticoid receptor (GR) expression in the hippocampus. Furthermore, stressed mice that also received paraquat displayed synergistic motor coordination impairment on a rotarod test and augmented signs of anhedonia (sucrose preference test). The individual stressor and paraquat treatments also caused a range of non-motor (e.g. open field, Y and plus mazes) deficits, but there were no signs of an interaction (neither additive nor synergistic) between the insults. Similarly, paraquat caused the expected loss of substantia nigra dopamine neurons and microglial activation, but this effect was not further influenced by the chronic stressor. Taken together, these results indicate that paraquat has many effects comparable to that of a more traditional stressor and that at least some behavioral measures (i.e. sucrose preference and rotarod) are augmented by the combined pesticide and stress treatments. Thus, although psychological stressors might not necessarily increase the neurodegenerative effects of the toxicant exposure, they may promote co-morbid behaviors pathology.

Animal Models of Depression: What Can They Teach Us about the Human Disease?

“…The most obvious feature of CMS that the animals manifest is anhedonia [ 106 , 107 ], demonstrated by sucrose intake and preference, which is reversed by chronic, but not by acute, antidepressant treatment [ 110 ]. Rodents exposed to CMS also exhibited hyperlocomotion in the open field test [ 107 ], shorter time spent in the open arm in EPM [ 108 ], and prolonged immobility time in the FST [ 109 ]. The CMS paradigm induces altered regulation of the hypothalamus–pituitary–adrenal (HPA) axis, changes in serotonergic, noradrenergic and dopaminergic systems, and reduced hippocampal BDNF level (details are reviewed by Hill et al) [ 111 ].…”

“…Induces both anxiety- and depression-like behaviors in FST, EPM, and sucrose preference tests [ 104 , 105 , 106 , 107 , 108 , 109 ].…”

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

“…The rotarod test and increased signs of anhedonia (sucrose preference test), where paraquat-treatment induced some non-motor symptoms in open-field, Y-maze, and plus-maze test defects without significant signs between the group of mice. They suggested that there is no interaction (additive or synergistic) between chronic unpredictable stress exposure and paraquat on behavioral and non-motor behavioral effects (except the rotarod test and 5th week of sucrose preference) [ 179 ]. Cristóvão et al (2020) administered paraquat 2.5 mg/kg/day, subcutaneously (osmotic minipump implanted in the back with 0.25 µL/h fluid delivery rate) for four weeks in male Wistar rats.…”

From Obesity to Hippocampal Neurodegeneration: Pathogenesis and Non-Pharmacological Interventions

“…Obese and diabetic animals show depression-like behaviors [ 90 , 91 , 92 ], which could be partly contributed by impaired hippocampal adult neurogenesis [ 93 , 94 , 95 ]. Both rodent models of depression [ 96 , 97 , 98 , 99 ] and diabetes [ 100 , 101 , 102 ] have shown a hyper-activated hypothalamic-pituitary-adrenal (HPA) axis, resulting in elevated glucocorticoid levels in response to stressors. The hippocampus exerts inhibitory feedback control to the activation of the HPA axis through GABAergic innervation to the paraventricular nucleus (PVN) of the hypothalamus [ 103 , 104 , 105 ].…”