Review : The Vicious Circle of Stress and Anticholinesterase Responses

Abstract

After either acute psychological stress or exposure to acetylcholinesterase (AChE) inhibitors, long-lasting deleterious changes of a similar nature occur in the mammalian brain. We explored the molecular and neurophysiological mechanisms preceding these convergent delayed consequences in vivo and in perfused hippocampal brain slices. In stressed mice, we observed a disruption of the blood-brain barrier, which leads to efficient brain penetrance of anti-AChEs. This increase in penetrance of anti-AChEs, and consequently in acetylcholine (ACh) levels, induces a cascade of c-fos-mediated transcriptional responses dependent on intracellular Ca²⁺ accumulation. Consequently, the capacity for synthesis and vesicle packaging of ACh is suppressed simultaneously with enhanced AChE production that potentiates ACh hydrolysis. This bimodal decrease in ACh bioavailability, which is independent of the hypothalamic-pituitary-adrenal axis, then ter minates the initial neurophysiological excitation. In vivo, this AChE overexpression leads to enzyme accu mulation that is evident for more than 80 hr. The overexpressed enzyme can protect the brain from sustained hyperexcitability and from increased susceptibility to seizure activity and neuronal toxicity. However, exper imental accumulation of AChE in brain neurons through transgenic manipulations leads to a slowly pro gressive deterioration in cognitive and neuromotor faculties. The transcriptional consequences of stress and anti-AChEs may therefore be beneficial in the short term but deleterious in the long term. NEURO SCIENTIST 5:173-183, 1999