It has been shown that inhibitors of acetylcholine (AC)-hydrolyzing enzyme acetylcholinesterase (Ache) may lead to the onset of post-traumatic stress disorder (PTSD). Prior to this study, no mechanism rrelating AC inhibition and stress had been explained. Kaufer et al. Showed that robust cholinergic stimulation, such as that due to stress, triggers the induction of PTSD. It had been previously shown that FVB/N mice subjected to forced swimming or inhibitors of Ache showed increased levels of c-Fos in the brain. Brain slices exposed to Ache inhibitors shoed enhanced neuronal excitability and increased cortical c-fos gene expression. These increases are mediated by stimulation of AC receptors. Thus there is a transient increase and delayed reduction in AC levels with stress. To determine whether AC inhibitors mediate acute and delayed cholinergic activity, Kaufer et al. Recorded extracellular potentials in the cell-body layer of the CA1 region of hippocampal slices. Potentials were evoked by orthodromic stimulation of the CA2/CA3 region of the stratum oriens enriched with cholinergic fibers. Exposure to Ache inhibitors increased spike amplitude, rate of rise and duration of paired-pulse facilitation. When Ache inhibition was extended, the population spikes were muted, suggesting that a delayed phase of suppressed neuronal activity follows the early phase of increased excitability. The c-fos gene has a Ca response element. Kaufer et al. proposed that neuronal excitability and /or intracellular CA accumulation lead to early cholinergic hyperactivity. Via a c-fos and Ca regulated feedback mechanism, AChe levels are eventually increased. This leads to abnormally low levels of AC which cause symptoms of PTSD such as depression, excitability an cognitive dysfunction. These effects are long-lasting. More studies need to be cone on these feedback pathways. The authors believe that these pathways may be associated with low-level exposure to anticholinesterase drugs and insecticides. Moreover, these pathways may explain the limited efficacy of cholinesterase inhibitors in treating Alzheimer’s disease.

REFERENCE:

Kaufer D, Friedman A, Seidman S, Soreq H: Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 1998 May 28;393(6683):373-377

RESOURCES:

Posttraumatic Stress Disorder; Description