Acute stress facilitates long-lasting changes in cholinergic gene expression

Abstract

Acute traumatic stress may lead to post-traumatic stress disorder (PTSD), which is characterized by delayed neuropsychiatric symptoms including depression, irritability, and impaired cognitive performance. Curiously, inhibitors of the acetylcholine-hydrolysing enzyme acetylcholinesterase may induce psychopathologies that are reminiscent of PTSD. It is unknown how a single stressful event mediates long-term neuronal plasticity. Moreover, no mechanism has been proposed to explain the convergent neuropsychological outcomes of stress and of acetylcholinesterase inhibition. However, acute stress elicits a transient increase in the amounts released of the neurotransmitter acetylcholine and a phase of enhanced neuronal excitability. Inhibitors of acetylcholinesterase also promote enhanced electrical brain activity, presumably by increasing the survival of acetylcholine at the synapse. Here we report that there is similar bidirectional modulation of genes that regulate acetylcholine availability after stress and blockade of acetylcholinesterase. These calcium-dependent changes in gene expression coincide with phases of rapid enhancement and delayed depression of neuronal excitability. Both of these phases are mediated by muscarinic acetylcholine receptors. Our results suggest a model in which robust cholinergic stimulation triggers rapid induction of the gene encoding the transcription factor c-Fos. This protein then mediates selective regulatory effects on the long-lasting activities of genes involved in acetylcholine metabolism.

Estimation of Plasma IC50 of Donepezil Hydrochloride for Brain Acetylcholinesterase Inhibition in Monkey Using N-[11C]methylpiperidin-4-yl Acetate ([11C]MP4A) and PET

“…It is reported that when living brain slices from mice were exposed to AChE inhibitors such as physostigmine and pyridostigmine, AChE mRNA levels were markedly increased 30 min after treatment, followed by enhancement of AChE in cerebral cortical regions (Kaufer et al, 1998). By this reason, we have performed two baseline experiments, once (baseline-1) before and once (baseline-2) after the donepezil administration.…”

Delayed‐onset post‐traumatic stress disorder symptoms in dementia

“…17 This may explain the therapeutic benefits of the antiglutamatergic agent memantine that has been observed in veterans with PTSD. Other studies also highlight the transient increase in the levels of acetyl choline and a phase of enhanced neuronal excitability following a period of stress, 18 possibly explaining the apparent exacerbation of PTSD symptoms in dementia patients who are taking acetylcholinesterase inhibitors. 19 Finally, with passage of time following trauma, PTSD patients also appear to show an increased fear response to a wide range of neutral cues, a phenomenon known as 'fear generalisation'.…”

Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly

“…30,40 Moreover it should also be mentioned that acetylcholinesterase inhibitors may induce psychopathologies reminiscent of posttraumatic stress disorders characterized by a series of neuropsychiatric symptoms including depression, 43 and also that stress has been shown to induce long lasting changes in cholinergic gene expression. 44 …”