Repeated stress in combination with pyridostigmine Part II: changes in cerebral gene expression

Organophosphates (OP) represent a potential threat in terrorism or during military conflicts. Due to its faculty to protect cholinesterase (ChE) activity against irreversible inactivation by OP, pyridostigmine bromide (PB) was used as a prophylaxis treatment during the first Persian Gulf War. To explain dysfunctions reported by Gulf War Veterans (GWV), it was suggested a potentiation of the operational stress effects by PB given to soldiers. Our companion paper (see part 1 in the same journal issue) describes that PB treatment administered in repeated stress conditions results in long-term perturbations of learning and social behaviour. The present paper examines, in adult male Wistar rats, consequences of the association of repeated stress and PB treatment on gene expression in hypothalamus and hippocampus. PB treatment (1.5 mg/kg/day) was orally administered 30 min before each stress session to inhibit 40% of blood ChE as recommended by NATO. 10 days of stress alone induce a decrease in hypothalamic Il-1alpha expression. Treatment with PB alone increases mineralocorticoid receptor expression in hypothalamus which means that PB may thus modify stress perception by animals. Stressed-PB animals showed increase in hippocampal expression of BDNF, TrkB and CamKIIalpha, three genes implicated in memory development. As a supplement to previous studies showing behavioural and biochemical effects of the association of stress with PB, our data reveal that behavioural effects of this association may be linked with genomic changes in hippocampus. Mechanisms underlying these modifications and their link with memory disturbances reported by GWV remain to be further determined.